Novel tricyclic hydroxy carboxamides and derivatives thereof tocolytic oxytocin receptor antagonists

ABSTRACT

This invention provides novel substituted tricyclic carboxamides which act as oxytocin receptor competitive antagonists, as well as methods of their manufacture, pharmaceutical compositions and methods of their use in treatment, inhibition, suppression or prevention of preterm labor, dysmenorrhea and endometritis, suppression of labor at term prior to caesarean delivery, and to facilitate antinatal transport to a medical facility. These compounds are also useful in enhancing fertility rates, enhancing survival rates and synchronizing estrus in farm animals; and may be useful in the prevention and treatment of disfunctions of the oxytocin system in the central nervous system including obsessive compulsive disorder (OCD) and neuropsychiatric disorders.

[0001] This application claims priority from copending provisionalapplication Serial No. 60/283,261, filed Apr. 12, 2001, the entiredisclosure of which is hereby incorporated by reference.

[0002] This invention concerns novel substituted tricyclic carboxamideswhich act as oxytocin receptor competitive antagonists, as well asmethods of their manufacture, methods of treatment and pharmaceuticalcompositions utilizing these compounds. The compounds of the presentinvention are useful therapeutic agents in mammals, particularly inhumans. More specifically, they can be used in the treatment and/orprevention and/or suppression of preterm labor and dysmenorrhea, for thesuppression of labor at term prior to caesarean delivery, and tofacilitate antinatal transport to a medical facility. These compoundsare also useful in enhancing fertility rates, enhancing survival ratesand synchronizing estrus in farm animals; and may be useful in theprevention and treatment of disfunctions of the oxytocin system in thecentral nervous system including obsessive compulsive disorder (OCD) andneuropsychiatric disorders.

BACKGROUND OF THE INVENTION

[0003] Premature labor remains the leading cause of perinatal mortalityand morbidity. Infant mortality dramatically decreases with increasedgestational age. The survival rate of prematurely born infants increasesfrom 20% at 24 weeks to 94% at 30 weeks. Moreover the cost associatedwith the care of an infant born prematurely is extremely high. Whilemany agents have been developed for the treatment of premature labor inthe last 40 years, the incidence of pre-term births and low birth weightinfants has remained relatively unchanged. Therefore there remains anunmet need for the development of a safe and effective treatment ofpreterm labor.

[0004] Tocolytic (uterine relaxing) agents currently in use include β₂adrenergic receptor agonists such as Ritodrine which is moderatelyeffective in suppressing preterm labor, but it is associated withmaternal hypotension, tachycardia, and metabolic side effects. Severalother agents have been used to suppress premature labor, including otherβ₂ adrenergic agonists (terbutaline, albuterol), magnesium sulfate,NSAIDs (indomethacin), and calcium channel blockers. The consensus isthat none of these agents are very effective; there is no clinicalevidence showing that these compounds can prolong gestation for morethan 7 days (Johnson, Drugs, 45, 684-692 (1993)). Furthermore, theirsafety profile is not ideal. Adverse effects include respiratorydepression and cardiac arrest (magnesium sulfate), hemodynamic effects(calcium channel blockers), premature closure of the ductus arteriosusand oligohydramnios (NSAIDs; prostaglandin synthase inhibitors).Therefore, there is an unmet need for safer and more efficacious agentsfor the treatment of preterm labor with better patient tolerability.Specific requirements with regard to safety include a product with no orlow rates of tachycardia, limited anxiety, improved fetal safety, andfew, if any, adverse cardiovascular effects.

[0005] One target of interest is the oxytocin receptor in the uterus,and a sefective oxytocin receptor antagonist has been proposed as anideal tocolytic agent. While the exact role of oxytocin (OT) inparturition has not been clearly defined, there is evidence stronglysuggesting that it may play a critical role in the initiation andprogression of labor in humans (Fuchs et al. Science 215, 1396-1398(1982); Maggi et al. J. Clin. EndocrinoL Metab. 70, 1142-1154 (1990);Akerlund, Reg. Pept 45,187-191 (1993); Akerlund, Int. Congr. Symp.Semin. Ser., Progress in Endocrinology 3, 657-660 (1993); Akerlund etal., in Oxytocin, Ed. R. Ivell and J. Russel, Plenum Press, New York, pp595-600 (1995)). Preliminary clinical trials with oxytocin receptorantagonists support the concept that a blockade of OT receptors reducesuterine myometrial activity and delays the onset of labor (Akerlund etal., Br. J. Obst. Gynaecol. 94, 1040-1044, (1987); Andersen et al., Am.J. Perinatol. 6, 196-199 (1989); Melin, Reg. Pept. 45, 285-288 (1993)).Thus, a selective oxytocin antagonist is expected to block the majoreffects of oxytocin exerted mainly on the uterus at term, and to be moreefficacious than current therapies for the treatment of preterm labor.By virtue of its direct action on the receptors in the uterus anoxytocin antagonist is also expected to have fewer side effects and animproved safety profile.

[0006] The following prior art references describe peptidic oxytocinantagonists: Hruby et al., Structure-Activity Relationships ofNeurohypophyseal Peptides, in The Peptides: Analysis, Synthesis andBiology, Udenfriend and Meienhofer Eds., Academic Press, New York, Vol.8, 77-207 (1987); Pettibone et al., Endocrinology, 125, 217 (1989);Manning et al., Synthesis and Some Uses of Receptor-Specific Agonistsand Antagonists of Vasopressin and Oxytocin, J. Recept. Res., 13,195-214 (1993); Goodwin et al., Dose Ranging Study of the OxytocinAntagonist Atosiban in the Treatment of Preterm Labor, Obstet. Gynecol.,88, 331-336 (1996). Peptidic oxytocin antagonists suffer from a lack oforal activity and many of these peptides are non-selective antagonistssince they also exhibit vasopressin antagonist activity. Bock et al. [J.Med. Chem. 33, 2321 (1990)], Pettibone et al. [J. Pharm. Exp. Ther. 256,304 (1991)], and Williams et al. [J. Med. Chem., 35, 3905 (1992)] havereported on potent hexapeptide oxytocin antagonists which also exhibitweak vasopressin antagonistic activity in binding to V₁ and V₂receptors.

[0007] Various non-peptidic oxytocin antagonists and/oroxytocin/vasopressin (AVP) antagonists have recently been reported byPettibone et al., Endocrinology, 125, 217 (1989); Yamamura et al.,Science, 252, 572-574 (1991); Evans et al., J. Med. Chem., 35, 3919-3927(1992); Pettibone et al., J. Pharmacol. Exp. Ther, 264, 308-314 (1992);Ohnishi et al., J. Clin. PharmacoL 33, 230-238, (1993); Evans et al., J.Med. Chem. 36, 3993-4006 (1993); Pettibone et al., Drug Dev. Res. 30,129-142 (1993); Freidinger et al., General Strategies in PeptidomimeticDesign: Applications to Oxytocin Antagonists, in Perspect. Med. Chem.179-193 (1993), Ed. B. Testa, Verlag, Basel, Switzerland;Serradeil-Legal, J. Clin. Invest., 92, 224-231 (1993); Williams et al.,J. Med. Chem. 37, 565-571 (1994); Williams et al., Bioorg. Med. Chem. 2,971-985 (1994); Yamamura et al., Br. J. Pharmacol., 105, 546-551 (1995);Pettibone et al., Advances in Experimental Medicine and Biology 395,601-612 (1995); Williams et al., J. Med. Chem. 38, 4634-4636 (1995);Hobbs et al., Biorg. Med. Chem. Lett. 5, 119 (1995); Williams et al.,Curr. Pharm. Des. 2, 41-58 (1996); Freidinger et al., Medicinal ResearchReviews, 17, 1-16 (1997); Pettibone et al., Biochem. Soc. Trans. 25 (3),1051-1057 (1997); Bell et al., J. Med. Chem. 41, 2146-2163 (1998); Kuoet al., Bioorg. Med. Chem. Left. 8, 3081-3086 (1998); Williams et al.,Biorg. Med. Chem. Left. 9, 1311-1316 (1999).

[0008] Certain carbostyril derivatives and bicyclic azepines aredisclosed as oxytocin and vasopressin antagonists by Ogawa et al. in WO94/01113 (1994); benzoxazinones are disclosed as oxytocin andvasopressin receptor antagonists by Sparks et al. in WO 97/25992 (1997);Williams et al. disclose piperidine oxytocin and vasopressin receptorantagonists in WO 96/22775 (1996); Bock et al. disclose benzoxazinoneand benzopyrimidinone piperidines useful as oxytocin and vasopressinreceptor antagonists in U.S. Pat. No. 5,665,719 (1997); piperazines andspiropiperidines useful as oxytocin and vasopressin receptor antagonistsare disclosed by Evans et al. in U.S, Patent 5,670,509 (1997) and byBock et al. in U.S. Pat. No. 5,756,504 (1998); Bell et al. disclosepiperazine oxytocin receptor antagonists in UK Patent Application, GB 2326 639 A (1998); Bell et al. disclose benzoxazinone and quinolinoneoxytocin and vasopressin receptor antagonists in UK Patent ApplicationGB 2 326 410 A (1998); Bell et al. disclose benzoxazinone oxytocin andvasopressin receptor antagonists in U.S. Pat. No. 5,756,497 (1998);Matsuhisa et al. disclose difluoro tetrahydrobenzazepine derivatives asoxytocin antagonists in WO 98/39325 (1998); Ogawa et al. discloseheterocyclic bisamides with vasopressin and oxytocin antagonist activityin U.S. Pat. No. 5,753,644 (1998); and Ogawa et al. disclose benzazepinederivatives with anti-vasopressin activity, oxytocin antagonisticactivity and vasopressin agonist activity, useful as vasopressinantagonists, vasopressin agonists and oxytocin antagonists in WO97/22591 (1997) and U.S. Pat. No. 6,096,736 (2000).

[0009] Trybulski et al. disclose 3-carboxamide derivatives ofpyrrolobenzodiazepine bisamides with vasopressin antagonist activity inU.S. Pat. No. 5,880,122 (1999); bicyclic thienoazepines with vasopressinand oxytocin receptor antagonist activity are disclosed by Albright etal. in WO 96/22294 (1996) and U.S. Pat. No. 5,654,297 (1997); andtricyclic benzazepines with vasopressin and oxytocin receptor antagonistactivity are disclosed by Albright et al. in U.S. Pat. No. 5,849,735(1998).

[0010] Albright et al. broadly disclose tricyclic benzazepinevasopressin antagonists in WO 96/22282A1 (1996) possessing antagonisticactivity at the VI and/or V₂ receptors and which exhibit in vivovasopressin antagonistic activity, as well as antagonistic activity atthe oxytocin receptors.

[0011] Venkatesan et al. broadly disclose tricyclic benzazepines withvasopressin and oxytocin antagonist activity in U.S. Pat. No. 5,521,173(1996), WO 96/22292 (1996), and in U.S.

[0012] Compounds which behave as potent oxytocin antagonists by bindingwith high affinity and selectivity to the oxytocin receptors, thuspreventing oxytocin from binding to its receptors and exerting itsbiological and pharmacologic effects in vivo, can be useful for thetreatment and/or prevention and/or suppression of preterm labor, for thesuppression of term labor prior to a caesarian delivery, and tofacilitate antinatal transport to a medical facility. They can alsoproduce contraception in mammals given that oxytocin antagonists havebeen shown to inhibit the release of oxytocin-stimulated luteneizinghormone (LH) from pituitary cells (Rettori et al., Proc. Nat. Acad. Sci.U.S.A. 94, 2741-2744 (1997); Evans et al., J. Endocrinol., 122, 107-116(1989); Robinson et al., J. Endocrinol. 125, 425-432 (1990)).

[0013] Oxytocin antagonists further have the ability to relax uterinecontractions induced by oxytocin in mammals and thus can be also usefulfor the treatment of dysmenorrhea, a condition characterized by painduring menstruation (Akerlund, Int. Congr. Symp. Semin. Ser., Progressin Endocrinology 3, 657-660 (1993); Akerlund, Reg. Pept. 45, 187-191(1993); Melin, Reg. Pept. 45, 285-288 (1993)). Primary dysmenorrhea isassociated with ovulatory cycles, and it is the most common complaint ofgynecologic patients. Myometrial hypercontractility and decreased bloodflow to the uterus are thought to be causative factors for for thesymptoms of primary dysmenorrhea (Åkerlund, Acta Obstet. Gynecol. Scand.66, 459-461 (1987). In particular, vasoconstriction of small uterinearteries by vasopressin and oxytocin is thought to produce tissueischemia and pain (Jovanovic et al., Br. J. Pharmacol. 12, 1468-1474(91997); Chen et al., Eur. J. Pharmacol. 376, 25-51 (1999)).

[0014] The administration of oxytocin receptor antagonists to farmanimals after fertilization has been found to enhance fertility rates byblocking oxytocin induced luteolysis leading to embryonic loss (Hickeyet al., WO 96/09824 μl (1996), Sparks et al., WO 97/25992 A1 (1997);Sparks et al., U.S. Pat. No. 5,726,172 A (1998)). Thus, oxytocinreceptor antagonists can be useful in farm animal husbandry to controltiming of parturition and delivery of newborns resulting in enhancedsurvival rates. They can also be useful for the synchronization ofestrus by preventing oxytocin induced corpus luteum regression and bydelaying estrus (Okano, J. Reprod. Dev. 42 (Suppl.), 67-70 (1996)).Furthermore oxytocin receptor antagonists have been found to have apowerful effect in inhibiting oxytocin-induced milk ejection in dairycows (Wellnitz et al., Journal of Dairy Research 66, 1-8 (1999)).

[0015] Oxytocin is also synthesized in the brain and released in thecentral nervous system. Recent studies have established the importanceof central oxytocin in cognitive, affiliative, sexual and reproductivebehavior, and in regulating feeding, grooming and response to stress inanimals. Oxytocin may also influence normal behavior in humans.Modulators of oxytocin binding to its receptors in the central nervoussystem may be useful in the prevention and treatment of disfunctions ofthe oxytocin system, including obsessive compulsive disorder (OCD) andother neuropsychiatric disorders (Kovacs et al.,Psychoneuroendocrinology 23, 945-962 (1998); McCarthy et al., U.K. Mol.Med. Today 3, 269-275 (1997); Bohus, Peptidergic Neuron, [Int. Symp.Neurosecretion], 12^(th) (1996), 267-277, Publ. Birkhauser, Basel,Switz.; Leckman et al., Psychoneuroendocrinology 19, 723-749 (1994)).

[0016] Compounds which act to competitively inhibit binding ofvasopressin to its receptors are useful in the treatment or preventionof state diseases involving vasopressin disorders in mammals, whichinclude vasodilation and aquaresis (free-water diuresis), treatinghypertension and inhibiting platelet aggregation. They are useful in thetreatment of congestive heart failure, cirrhosis with ascites, and inthe syndrome of inappropriate secretion of antiduretic hormone (SIADH).Furthermore, vasopressin receptor antagonists have been found to beuseful in treating disturbances or illnesses of the inner ear,particularly those related to Meniere's disease (Zenner et al., WO99/24051-A2 (1999)); and for the prevention and treatment of ocularcirculatory disorders, particularly intraocular hypertension or glaucomaand vision disorders such as shortsightedness (Ogawa et al., WO99/38533-Al (1999); Ohtake et al., WO 99/65525 (1999)).

SUMMARY OF THE INVENTION

[0017] This invention comprises novel compounds selected from those ofFormula (I):

[0018] wherein:

[0019] is selected from the moieties:

[0020] R₁ and R₂ are, independently, selected from hydrogen,(C₁-C₆)lower alkyl, halogen, cyano, trifluoromethyl, hydroxy, amino,(C₁-C₆) lower alkylamino, (C₁-C₆) lower alkoxy, —OCF₃, (C₁-C₆) loweralkoxycarbonyl, —NHCO[(C₁-C₆)lower alkyl], carboxy, —CONH₂,—CONH[(C₁-C₆) lower alkyl] or —CON-[(C₁-C₆) lower alkyl]₂;

[0021] R₃ is a substituent selected from hydrogen, (C₁-C₆) lower alkyl,(C₁-C₆) lower alkoxy, hydroxy, amino, (C₁-C₆) lower alkylamino, —COlower alkyl (C₁-C₆), or halogen;

[0022] R₄ consists of the moiety B-C; wherein:

[0023] B is selected from the group consisting of:

[0024] and C is selected from the group consisting of:

[0025] wherein:

[0026] A is CH or N;

[0027] R₅, R₆, R₇, R₈, R₉, R₁₀ are, independently, selected fromhydrogen, (C₁-C₆) lower alkyl, (C₁-C₆) lower alkoxy, hydroxy (C₁-C₆)lower alkyl, alkoxy (C₁-C₆) lower alkyl, acyloxy (C₁-C₆) lower alkyl,(C₁-C₆) lower alkylcarbonyl, (C₃-C₆) lower alkenyl, (C₃-C₆) loweralkynyl, (C₃-C₈) cycloalkyl, formyl, cycloalkylcarbonyl, carboxy, loweralkoxycarbonyl, cycloalkyloxycarbonyl, aryl alkyloxycarbonyl, carbamoyl,—O—CH₂—CH═CH₂, halogen, halo lower alkyl, trifluoromethyl, —OCF₃,—S[(C₁-C₆) lower alkyl], —OC(O)N-[(C₁-C₆) lower alkyl]₂, —CONH[(C₁-C₆)lower alkyl], —CON-[(C₁-C₆) lower alkyl]₂, (C₁-C₆) lower alkylamino,di-[(C₁-C₆) lower alkyl]amino, (C₁-C₆) lower alkyl di-[(C₁-C₆) loweralkyl]amino, hydroxy, cyano, trifluoromethylthio, nitro, amino, (C₁-C₆)lower alkylsulfonyl, aminosulfonyl, (C₁-C₆) lower alkylaminosulfonyl,

[0028] phenyl or naphthyl;

[0029] R₁₁ and R₁₂ are, independently, selected from the group ofhydrogen, (C₁-C₆) lower alkyl, (C₃-C₆) lower alkenyl, (C₁-C₆) loweralkynyl, cyclo lower alkyl, or aryl, optionally substituted by hydroxy,(C₁-C₆) lower alkyl, (C₁-C₆) lower alkoxy, halogen, cyano, —SO₂[(C₁-C₆)lower alkyl], or —S[(C₁-C₆) lower alkyl];

[0030] R is selected, independently, from any of the following groups:

[0031] R₁₃ is selected from hydrogen, (C₁-C₆) lower alkyl, (C₇-C₁₂) aryllower alkyl wherein the aryl moiety is optionally substituted with loweralkoxy, or any of the following groups:

[0032] R₁₄ is selected from any of the following groups:

[0033] R₁₅ and R₁₆ are, independently, chosen from the group ofhydrogen, (C₁-C₆) lower alkyl or (C₇-C₁₂) aryl lower alkyl;

[0034] R₁₇ is hydrogen, or (C₁-C₆) lower alkyl;

[0035] R₁₈ is hydroxy, lower alkoxy, or OP wherein P is a hydroxyprotecting group, defined as a group providing temporary protectionagainst undesirable reactions during synthetic procedures and to beselectively removable. Common hydroxy protecting groups include, but arenot limited to, tert-butyldimethylsilyl, tert-butyldiphenylsilyl,acetyl, trifluoroacetyl, benzyl, benzoyl, methoxymethyl,methylthiomethyl, and others well known in the art (such as those setforth in c.f. Greene et al., Protective Groups in Organic Syntheses, 3rdEdn., John Wiley & Sons, New York (1999), the text of which isincorporated herein by reference);

[0036] R₁₉ is selected from the group of hydrogen, (C₁-C₆) lower alkylor (C₇-C₁₂) aryl lower alkyl;

[0037] R₂₀ is selected from the group of-N-[lower alkyl]₂, or —N-[aryllower alkyl]₂;

[0038] R₂₁ is hydrogen, (C₁-C₆) lower alkyl, or R₂₉;

[0039] R₂₂ is selected from the group of (C₁-C₆) lower alkyl, —COR₁₈,—CONH[lower alkyl], —CON-[lower alkyl]₂;

[0040] R₂₃ is aryl, optionally substituted by one to three substituentschosen from hydroxy, (C₁-C₆) lower alkoxy, aryloxy lower alkyl, orhalogen;

[0041] R₂₄ represents one to four substituents chosen, independently,from the group consisting of hydrogen or (C₁-C₆) lower alkyl;

[0042] R₂₅ is selected the group consisting of

[0043] R₂₆ is (C₁-C₆) lower alkyl, or aryl (C₁-C₆) lower alkyl;

[0044] R₂₇ and R₂₈ taken together represent one to four substituentschosen, independently, from the group consisting of R₁₈, R₂₉, (C₁-C₆)lower alkyl , [(C₁-C₆) lower alkyl]₂, —CONH[lower alkyl], —CON-[loweralkyl]₂, R₃₂, or

[0045]  with the proviso that at least one substituent is not (C₁-C₆)lower alkyl, -[(C₁-C₆) lower alkyl]₂, —CONH[lower alkyl] or —CON-[loweralkyl]₂; and with further proviso that R₂₇ and R₂₈ can be joinedtogether to form a 5 or 6 membered saturated ring optionally substitutedby one or more substituents selected from R₁₈ or R₂₉;

[0046] R₂₉ is selected from the group of hydroxy lower alkyl, loweralkoxy lower alkyl, or lower alkyl OP wherein P is a hydroxy protectinggroup, defined as a group providing temporary protection againstundesirable reactions during synthetic procedures and to be selectivelyremovable. Common hydroxy protecting groups include, but are not limitedto, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, acetyl,trifluoroacetyl, benzyl, benzoyl, methoxymethyl, methylthiomethyl, andothers well known in the art (c.f. Greene et al., Protective Groups inOrganic Syntheses, 3rd Edn., John Wiley & Sons, New York (1999);

[0047] R₃₀ is (C₁-C₆) lower alkyl, or (C₇-C₁₂) aryl lower alkyl;

[0048] R₃₁ represents one to four substituents chosen from the group ofR₁₈ or R₂₉;

[0049] R₃₃ is hydrogen or (C₁-C₆) lower alkyl;

[0050] X and Y are either CH, or N;

[0051] p is an integer from 0 to 1;

[0052] q is an integer from 2 to 4;

[0053] r is an integer from 0 to 3;

[0054] s in integer from 0 to 2

[0055] t is an integer from 1 to 2;

[0056] and the pharmaceutically acceptable salts, or pro-drug formsthereof.

[0057] One group of compounds of this invention comprise those of theformula (II):

[0058] wherein R, R₁, R₂, R₃, R₅, R₆, R₇, R₈, R₉, R₁₀ are as definedabove, or a pharmaceutically acceptable salt form thereof.

[0059] One preferred group of compounds of this invention are those ofthe formula:

[0060] wherein:

[0061] is selected from the moieties:

[0062] R₁ and R₂ are, independently, selected from hydrogen,(C₁-C₆)lower alkyl, halogen, cyano, trifluoromethyl, hydroxy, amino,(C₁-C₆) lower alkylamino, (C₁-C₆) lower alkoxy, —OCF₃, (C₁-C₆) loweralkoxycarbonyl, —NHCO[(C₁-C₆)lower alkyl], carboxy, —CONH₂,—CONH[(C₁-C₆) lower alkyl] or —CON-[(C₁-C₆) lower alkyl]₂;

[0063] R₃ is a substituent selected from hydrogen, (C₁-C₆) lower alkyl,(C₁-C₆) lower alkoxy, hydroxy, amino, (C₁-C₆) lower alkylamino, —COlower alkyl (C₁-C₆), or halogen;

[0064] R₄ consists of the moiety B-C; wherein:

[0065] B is selected from the group consisting of:

[0066] and C is selected from the group consisting of:

[0067] wherein:

[0068] A is CH or N;

[0069] R₅, R₆, R₇, R₈, R₉, R₁₀ are, independently, selected fromhydrogen, (C₁-C₆) lower alkyl, (C₁-C₆) lower alkoxy, hydroxy (C₁-C₆)lower alkyl, alkoxy (C₁-C₆) lower alkyl, acyloxy (C₁-C₆) lower alkyl,(C₁-C₆) lower alkylcarbonyl, (C₃-C₆) lower alkenyl, (C₃-C₆) loweralkynyl, (C₃-C₈) cycloalkyl, formyl, cycloalkylcarbonyl, carboxy, loweralkoxycarbonyl, cycloalkyloxycarbonyl, aryl alkyloxycarbonyl, carbamoyl,—O—CH₂—CH═CH₂, halogen, halo lower alkyl, trifluoromethyl, —OCF₃,—S[(C₁-C₆) lower alkyl], —OC(O)N-[(C₁-C₆) lower alkyl]₂, —CONH[(C₁-C₆)lower alkyl], —CON-[(C₁-C₆) lower alkyl]₂, (C₁-C₆) lower alkylamino,di-[(C₁-C₆) lower alkyl]amino, (C₁-C₆) lower alkyl di-[(C₁-C₆) loweralkyl]amino, hydroxy, cyano, trifluoromethylthio, nitro, amino, (C₁-C₆)lower alkylsulfonyl, aminosulfonyl, (C₁-C₆) lower alkylaminosulfonyl,

[0070] phenyl or naphthyl;

[0071] R₁₁ and R₁₂ are, independently, selected from the group ofhydrogen, (C₁-C₆) lower alkyl, (C₃-C₆) lower alkenyl, (C₁-C₆) loweralkynyl, cyclo lower alkyl, or aryl, optionally substituted by hydroxy,(C₁-C₆) lower alkyl, (C₁-C₆) lower alkoxy, halogen, cyano, —SO₂[(C₁-C₆)lower alkyl], or —S[(C₁-C₆) lower alkyl];

[0072] R is selected, independently, from the groups:

[0073] R₁₃ is selected from hydrogen, (C₁-C₆) lower alkyl, (C₇-C₁₂) aryllower alkyl wherein the aryl moiety is optionally substituted with loweralkoxy, or any of the following groups:

[0074] R₁₄ is selected from the groups:

[0075] R₁₅ and R₁₆ are, independently, chosen from the group ofhydrogen, (C₁-C₆) lower alkyl or (C₇-C₁₂) aryl lower alkyl;

[0076] R₁₈ is hydroxy, lower alkoxy, or OP wherein P is a hydroxyprotecting group, defined as a group providing temporary protectionagainst undesirable reactions during synthetic procedures and to beselectively removable. Common hydroxy protecting groups include, but arenot limited to, tert-butyidimethylsilyl, tert-butyldiphenylsilyl,acetyl, trifluoroacetyl, benzyl, benzoyl, methoxymethyl,methylthiomethyl, and others well known in the art (such as those setforth in c.f. Greene et al., Protective Groups in Organic Syntheses, 3rdEdn., John WiJey & Sons, New York (1999), the text of which isincorporated herein by reference);

[0077] R₁₉ is selected from the group of hydrogen, (C₁-C₆) lower alkylor (C₇-C₁₂) aryl lower alkyl;

[0078] R₂₁ is hydrogen, (C₁-C₆) lower alkyl, or R₂₉;

[0079] R₂₅ is selected from the groups:

[0080] R₂₆ is (C₁-C₆) lower alkyl, or aryl (C₁-C₆) lower alkyl;

[0081] R₂₉ is selected from the group of hydroxy lower alkyl, loweralkoxy lower alkyl, or lower alkyl OP wherein P is a hydroxy protectinggroup, defined as a group providing temporary protection againstundesirable reactions during synthetic procedures and to be selectivelyremovable. Common hydroxy protecting groups include, but are not limitedto, tert-butyidimethylsilyl, tert-butyidiphenylsilyl, acetyl,trifluoroacetyl, benzyl, benzoyl, methoxymethyl, methylthiomethyl, andothers well known in the art (c.f. Greene et al., Protective Groups inOrganic Syntheses, 3rd Edn., John Wiley & Sons, New York (1999);

[0082] p is an integer from 0 to 1;

[0083] q is an integer from 2 to 4;

[0084] t is an integer from 1 to 2;

[0085] or a pharmaceutically acceptable salt or pro-drug form thereof.

[0086] A further preferred subgroup of the compounds described above arethose of the formula:

[0087] R₁ and R₂ are, independently, selected from hydrogen,(C₁-C₆)lower alkyl, halogen, cyano, trifluoromethyl, hydroxy, amino,(C₁-C₆) lower alkylamino, (C₁-C₆) lower alkoxy, —OCF₃, (C₁-C₆) loweralkoxycarbonyl, —NHCO[(C₁-C₆)lower alkyl], carboxy, —CONH₂,—CONH[(C₁-C₆) lower alkyl] or —CON-[(C₁-C₆) lower alkyl]₂;

[0088] R₃ is a substituent selected from hydrogen, (C₁-C₆) lower alkyl,(C₁-C₆) lower alkoxy, hydroxy, amino, (C₁-C₆) lower alkylamino, —COlower alkyl (C₁-C₆), or halogen;

[0089] R₄ consists of the moiety B-C; wherein:

[0090] B is selected from the group consisting of:

[0091] and C is selected from the group consisting of:

[0092] wherein:

[0093] A is CH or N;

[0094] R₅, R₆, R₇, R₈, R₉, R₁₀ are, independently, selected fromhydrogen, (C₁-C₆) lower alkyl, (C₁-C₆) lower alkoxy, hydroxy (C₁-C₆)lower alkyl, alkoxy (C₁-C₆) lower alkyl, acyloxy (C₁-C₆) lower alkyl,(C₁-C₆) lower alkylcarbonyl, (C₃-C₆) lower alkenyl, (C₃-C₆) loweralkynyl, (C₃-C₈) cycloalkyl, formyl, cycloalkylcarbonyl, carboxy, loweralkoxycarbonyl, cycloalkyloxycarbonyl, aryl alkyloxycarbonyl, carbamoyl,—O—CH₂—CH═CH₂, halogen, halo lower alkyl, trifluoromethyl, —OCF₃,—S[(C₁-C₆) lower alkyl], —OC(O)N-[(C₁-C₆) lower alkyl]₂, —CONH[(C₁-C₆)lower alkyl], —CON-[(C₁-C₆) lower alkyl]₂, (C₁-C₆) lower alkylamino,di-[(C₁-C₆) lower alkyl]amino, (C₁-C₆) lower alkyl di-[(C₁-C₆) loweralkyl]amino, hydroxy, cyano,trifluoromethylthio, nitro, amino, (C₁-C₆)lower alkylsulfonyl, aminosulfonyl, (C₁-C₆) lower alkylaminosulfonyl,

[0095] phenyl or naphthyl;

[0096] R₁₁ and R₁₂ are, independently, selected from the groupofhydrogen, (C₁-C₆) lower alkyl, (C₃-C₆) lower alkenyl, (C₁-C₆) loweralkynyl, cyclo lower alkyl, or aryl, optionally substituted by hydroxy,(C₁-C₆) lower alkyl, (C₁-C₆) lower alkoxy, halogen, cyano, —SO₂[(C₁-C₆)lower alkyl], or —S[(C₁-C₆) lower alkyl];

[0097] R is selected, independently, from the groups:

[0098] R₁₃ is selected from hydrogen, (C₁-C₆) lower alkyl, (C₇-C₁₂) aryllower alkyl wherein the aryl moiety is optionally substituted with loweralkoxy, or any of the following groups:

[0099] R₁₄ is selected from the groups:

[0100] R₁₅ and R₁₆ are, independently, chosen from the group ofhydrogen, (C₁-C₆) lower alkyl or (C₇-C₁₂) aryl lower alkyl;

[0101] R₁₈ is hydroxy, lower alkoxy, or OP wherein P is a hydroxyprotecting group, defined as a group providing temporary protectionagainst undesirable reactions during synthetic procedures and to beselectively removable. Common hydroxy protecting groups include, but arenot limited to, tert-butyldimethylsilyl, tert-butyldiphenylsilyl,acetyl, trifluoroacetyl, benzyl, benzoyl, methoxymethyl,methylthiomethyl, and others well known in the art (such as those setforth in c.f. Greene et al., Protective Groups in Organic Syntheses, 3rdEdn., John Wiley & Sons, New York (1999), the text of which isincorporated herein by reference);

[0102] R₁₉ is selected from the group of hydrogen, (C₁-C₆) lower alkylor (C₇-C₁₂) aryl lower alkyl;

[0103] R₂₁ is hydrogen, (C₁-C₆) lower alkyl, or R₂₉;

[0104] R₂₅ is selected from the groups:

[0105] R₂₆ is (C₁-C₆) lower alkyl, or aryl (C₁-C₆) lower alkyl;

[0106] R₂₉ is selected from the group of hydroxy lower alkyl, loweralkoxy lower alkyl, or lower alkyl OP wherein P is a hydroxy protectinggroup, defined as a group providing temporary protection againstundesirable reactions during synthetic procedures and to be selectivelyremovable. Common hydroxy protecting groups include, but are not limitedto, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, acetyl,trifluoroacetyl, benzyl, benzoyl, methoxymethyl, methylthiomethyl, andothers well known in the art (c.f. Greene et al., Protective Groups inOrganic Syntheses, 3rd Edn., John Wiley & Sons, New York (1999);

[0107] p is an integer from 0 to 1;

[0108] q is an integer from 2 to 4;

[0109] t is an integer from 1 to 2;

[0110] or a pharmaceutically acceptable salt or pro-drug form thereof.

[0111] Within each of the groups described herein is a further subset ofcompounds wherein R₃ is hydrogen.

[0112] In another additional subset within each group herein is one inwhich R is the moiety:

[0113] wherein A, R₅, R₆, R₇, R₈, R₉, and R₁₀ are as defined above.Within these groups are a further preferred group wherein R is themoiety:

[0114] As used herein the term “lower” in relation to alkoxy or alkyl isunderstood to refer to those groups having from 1 to 6 carbon atoms.Halogen refers to fluorine, chlorine, bromine or iodine.

[0115] It is understood by those practicing the art that some of thecompounds of this invention depending on the definition of R₁, R₂, R₃,R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, and R₁₂, may contain one or moreasymmetric centers and may thus give rise to enantiomers anddiastereomers. The present invention includes all stereoisomersincluding individual diastereomers and resolved, enantiomerically pure Rand S stereoisomers; as well as racemates, and all other mixtures of theR and S stereoisomers and pharmaceutically acceptable salts thereof,which possess the indicated activity. Optical isomers may be obtained inpure form by standard procedures known to those skilled in the art. Itis also understood that this invention encompasses all possibleregioisomers, E-Z isomers, endo-exo isomers, and mixtures thereof whichpossess the indicated activity. Such isomers may be obtained in pureform by standard separation procedures known to those skilled in theart. It is understood also by those practicing the art that some of thecompounds of this invention depending on the definition of R₅, R₆, R₈,R₉, R₁₀, R₁₁, and R₁₂ may be chiral due to hindered rotation, and giverise to atropisomers which can be resolved and obtained in pure form bystandard procedures known to those skilled in the art. Also included inthe present invention are all polymorphs and hydrates of the compoundsof the present invention.

DETAILED DESCRIPTION OF THE INVENTION

[0116] The present invention comprises the compounds described above, aswell as pharmaceutical compositions comprising one or more compounds ofthis invention in combination or association with one or morepharmaceutically acceptable carriers or excipients. In particular, thepresent invention provides a pharmaceutical composition which comprisesa pharmaceutically or therapeutically effective amount of one or morecompounds of this invention in a pharmaceutically acceptable carrier orexcipient.

[0117] This invention also comprises methods for treating, inhibiting orpreventing conditions in a mammal, preferably a human, which areremedied or alleviated by oxytocin antagonist activity including, butnot limited to, treatment, inhibition or prevention of preterm labor,dysmenorrhea and suppressing labor prior to caesarian delivery wheneverdesirable in a mammal, preferably in a human. The methods compriseadministering to a mammal in need thereof a therapeutically effectivebut non-toxic amount of one or more of the compounds of this invention.

[0118] The present invention also comprises combinations of thecompounds of the present invention with one or more agents useful in thetreatment of disorders such as preterm labor, dysmenorrhea, and stoppinglabor prior to caesarian delivery. More specifically, the compounds ofthe present invention may be effectively administered in combinationwith effective amounts of other tocolytic agents used in the treatment,inhibition or prevention of preterm labor, dysmenorrhea or suppressinglabor prior to caesarean delivery including β-adrenergic agonists,calcium channel blockers, prostaglandin synthesis inhibitors, otheroxytocin antagonists (e.g. atosiban), magnesium sulfate, ethanol, andother agents useful in the treatment of said disorders. The presentinvention is to be understood as embracing all simultaneous oralternating treatments of any combination of the compounds of thepresent invention with other tocolytic agents with any pharmaceuticalcomposition useful for the treatment of preterm labor, dysmenorrhea, andsuppressing labor prior to caesarean delivery in mammals.

[0119] The compositions are preferably adapted for intravenous (bothbolus and infusion) and oral administration. However, they may beadapted for other modes of administration including subcutaneous,intraperitoneal, or intramuscular administration to a human or a farmanimal in need of a tocolytic agent.

[0120] The compounds of the present invention can be used in the form ofsalts derived from non toxic pharmaceutically acceptable acids or bases.These salts include, but are not limited to, the following: salts withinorganic acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid and, as the case may be, such organicacids as acetic acid, oxalic acid, citric acid, tartaric acid, succinicacid, maleic acic, benzoic acid, benzene sulfonic acid, fumaric acid,malic acid, methane sulfonic acid, pamoic acid, and para-toluensulfonicacid. Other salts include salts with alkali metals or alkaline earthmetals, such as sodium, potassium, calcium or magnesium, or with organicbases including quaternary ammonium salts. The compounds can also beused in the form of esters, carbamates and other conventional prodrugforms, which in general, will be functional derivatives of the compoundsof this invention which are readily converted to the active moiety invivo. This is meant to include the treatment of the various conditionsdescribed hereinbefore with a compound of this invention or with acompound which is not specifically disclosed but which converts to acompound of this invention in vivo upon administration. Also includedare metabolites of the compounds of the present invention defined asactive species produced upon introduction of these compounds into abiological system.

[0121] When the compounds of this invention are employed for the aboveutilities, they may be combined with one or more pharmaceuticallyacceptable excipients or carriers, for example, solvents, diluents andthe like, and may be administered orally in such forms as tablets,capsules (including time release and sustained release formulations),pills, dispersible powders, granules, or suspensions containing, forexample, from 0.05 to 5% of suspending agent, syrups containing, forexample, from about 10 to 50% of sugar, and elixirs and the like, orparenterally in the form of sterile injectable solutions, suspensions oremulsions containing from about 0.05 to 5% suspending agent in anisotonic medium. Such pharmaceutical preparations may contain, forexample, from about 25 to about 90% of the active ingredient incombination with the carrier, more usually between about 5% and 60% byweight.

[0122] The effective dosage of active ingredients employed may varydepending on the particular compound or salt employed, the mode ofadministration, age, weight, sex and medical condition of the patient,and the severity of the condition being treated. An ordinarily skilledphysician, veterinarian or clinician can readily determine and prescribethe effective amount of the agent required to prevent, counter or arrestthe progress of the condition. However, in general, satisfactory resultsare obtained when the compounds of the invention are administered at adaily dose of from about 0.5 to about 500 mg/Kg of mammal body weight,preferably given in divided doses two to four times a day, or in asustained release form. For most large mammals the total daily dosage isfrom about 0.5 to 100 mg, preferably from 0.5 to 80 mg/Kg. Dosage formssuitable for internal use comprise from about 0.05 to 500 mg of theactive compound in intimate admixture with a solid or liquidpharmaceutically acceptable carrier. This dosage regimen may be adjustedto provide the optimal therapeutic response. For example, severaldivided doses may be administered daily or the dose may beproportionally reduced as indicated by the exigencies of the therapeuticsituation.

[0123] These active compounds may be administered orally as well as byintravenous, intramuscular, or subcutaneous routes. Solid carriersinclude starch, lactose, dicalcium phosphate, microcrystallinecellulose, sucrose and kaolin, while liquid carriers include sterilewater, polyethylene glycols, glycerol, non-ionic surfactants and edibleoils such as corn, peanut and sesame oils, as are appropriate to thenature of the active ingredient and the particular form ofadministration desired. Adjuvants customarily employed in thepreparation of pharmaceutical compositions may be advantageouslyincluded, such as flavoring agents, coloring agents, preserving agents,and antioxidants, for example vitamin E, ascorbic acid, BHT and BHA.

[0124] These active compounds may also be administered parenterally orintraperitoneally. Solutions or suspensions of these active compounds asa free base or pharmacologically acceptable salt can be prepared inwater suitably mixed with a surfactant such as hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparations contain a preservative to preventthe growth of microorganisms.

[0125] The pharmaceutical forms suitable for injectable use includesterile aqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy injectability exists. It must be stable underconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol (e.g. glycerol, propylene glycol, and liquid polyethyleneglycol), suitable mixtures thereof, and vegetable oil.

[0126] Furthermore, active compounds of the present invention can beadministered intranasally using vehicles suitable for intranasaldelivery, or transdermally using transdermal skin patches known to thoseordinarily skilled in the art. When using a transdermal delivery system,the dosage administration will be continuous rather than in a single ordivided daily doses. The compounds of the present invention can also beadministered in the form of liposome delivery system wherein theliposomal lipid bilayers are formed from a variety of phospholipids.

[0127] Compounds of the present invention may also be delivered by theuse of carriers such as monoclonal antibodies to which the activecompounds are coupled. The compounds of the present invention may alsobe coupled to soluble polymers as drug carriers or to biodegradablepolymers useful in achieving controlled release of the active agent.

[0128] Also according to the present invention there are providedprocesses for producing the compounds of the present invention.

PROCESS OF THE INVENTION

[0129] The compounds of the present invention may be prepared accordingto one of the general processes outlined below.

[0130] The compounds of general formula (I) wherein R₄ consists of themoiety B-C, where B is selected from the group (a) or (b) and C isselected from the group of (c), (d), (e) and (f) defined hereinbefore,can be conveniently prepared as shown in Scheme I.

[0131] According to the above preferred process, a tricyclic azepine offormula (I) wherein

[0132] R₃ and R₄ are defined hereinbefore, is reacted withperhaloalkanoyl halide preferably trichloroacetyl chloride, in thepresence of an organic base such as N,N-diisopropylethyl amine (Hünig'sbase), in an aprotic organic solvent such as dichloromethane, attemperatures ranging from −10° C. to ambient to provide the desiredtrichloroacetyl intermediate of formula (2). Subsequent hydrolysis of(2) with aqueous base such as sodium hydroxide in an organic solventsuch as tetrahydrofuran or acetone at temperatures ranging from −10° C.to ambient, yields the intermediate acid of formula (3). The requiredactivation of the carboxylic acid (3) for the subsequent coupling with aprimary or secondary amine of formula (5) can be accomplished in severalways. Thus, (3) can be converted to an acid halide preferable a chlorideor bromide of formula (4, J=COCl or COBr) by reaction with thionylchloride(bromide) or oxalyl chloride(bromide) or similar reagents knownin the art, either neat or in the presence of an inorganic base such aspotassium carbonate, or in the presence of an organic base such aspyridine, 4-(dimethylamino)pyridine, or a tertiary amine such astriethylamine, in an aprotic solvent such as dichloromethane,N,N-dimethylformamide or tetrahydrofuran, at temperatures ranging from−5° C. to 50° C. to yield the intermediate acylated derivative (4).Subsequent coupling of the acid chloride(bromide) (4, J=COCl or COBr)with an appropriately substituted primary or secondary amine of formula(5) in the presence of a stoichiometric amount of Hunig's base, in anaprotic solvent such as dichloromethane, N,N-dimethylformamide ortetrahydrofura, at temperatures ranging from ambient to the refluxtemperature of the solvent provides the desired compounds of formula (I)wherein

[0133] R, R₃ and R₄ are as defined hereinbefore.

[0134] Alternatively, the acylating species can be a mixed anhydride ofthe corresponding carboxylic acid, such as that prepared by treatingsaid acid of formula (3) with 2,4,6-trichlorobenzoyl chloride, in anaprotic organic solvent such as dichloromethane, according to theprocedure of Inanaga et al., Bull. Chem. Soc. Jpn. 52, 1989 (1979).Treatment of said mixed anhydride of formula (4) with an appropriatelysubstituted primary or secondary amine of formula (5) in an aproticsolvent such as dichloromethane, at temperatures ranging from ambient tothe reflux temperature of the solvent provides the desired compounds offormula (I) wherein

[0135] R, R₃ and R₄ are as defined hereinbefore.

[0136] Alternatively, amidation of the carboxylic acids of formula (3)can be effectively carried out by treatment of said acid withtriphosgene, in an aprotic solvent such as dichloromethane, followed byreaction of the activated intermediate with an appropriately substitutedprimary or secondary amine of formula (5), in the presence of an organicbase such as Hünig's base, at temperatures ranging from −10° C. toambient.

[0137] Another preferred process for the preparation of the compounds ofthe present invention of formula (I) wherein

[0138] R, R₃ and R₄ are as defined hereinbefore, consists of treatingthe acid of formula (3) with an activating reagent such asN,N-dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride, in the presence of 1-hydroxybenzotriazole,followed by reaction of the activated intermediate with an appropriatelysubstituted primary or secondary amine of formula (5), preferably in thepresence of an organic base such as Hunig's base and a catalytic amountof 4-(dimethylamino)pyridine, in an aprotic solvent such asdichloromethane, N,N-dimethylformamide or tetrahydrofuran, attemperatures ranging from −10° C. to ambient.

[0139] In another preferred process, said acid (3) can be activated bytreatment with other activating agents such as N,N′-carbonyldiimidazole,in an aprotic solvent such as dichloromethane or tetrahydrofuran, attemperatures ranging from −10° C. to the reflux temperature of thesolvent. Subsequent reaction of the intermediate activated imidazolidewith an appropriately substituted primary or secondary amine of formula(5) provides the desired compounds of formula (I), wherein

[0140] R, R₃ and R₄ are as defined hereinbefore.

[0141] Alternatively, the coupling of the appropriately substitutedprimary or secondary amine of formula (5) with said acid of formula (3)can be effectively carried out by using hydroxybenzotriazoletetramethyluronium hexafluorophosphate as the coupling reagent, in thepresence of an organic base such as Hünig's base, and in a solvent suchas N,N-dimethylformamide, at temperatures ranging from −10° C. toambient to provide in good isolated yield and purity the desiredcompounds of formula (I) wherein

[0142] R, R₃ and R₄ are as defined hereinbefore.

[0143] Related coupling reagents such as diphenylphosphoryl azide,diethyl cyano phosphonate, benzotriazol-1-yl-oxy-tris-(dimethylamino)phosphonium hexafluorophosphate and all other reagents known in theliterature that have been used in the formation of amide bonds inpeptide synthesis can also be used for the preparation of compounds offormula (I) wherein

[0144] R, R₃ and R₄ are as defined hereinbefore.

[0145] As an alternative, reaction of the intermediate3-trihalomethylketone of formula (2) directly with an appropriatelysubstituted primary or secondary amine of formula (5) also provides thedesired compounds of formula (I) wherein

[0146] R, R₃ and R₄ are as defined hereinbefore.

[0147] The method of choice for the preparation of compounds of formula(I) from the intermediate carboxylic acid (3) is ultimately chosen onthe basis of its compatibility with the R, R₃ and R₄ groups, and itsreactivity with the tricyclic diazepine of formula (I).

[0148] Another preferred process for the preparation of (I) of Scheme Iis shown in Scheme II. A tricyclic diazepine of formula (I) is reactedwith diphosgene in an aprotic solvent such as dichloromethane,preferably in the presence of an organic base such as triethylamine,followed by reaction of the resulting acylated intermediate with anappropriately substituted primary or secondary amine of formula (5), toprovide the desired compounds of formula (I) wherein

[0149] R, R₃ and R₄ are as defined hereinbefore.

[0150] The tricyclic diazepines of formula (I) of Scheme I wherein R₄ ischosen on the basis of its compatibility with the reaction scheme, canbe conveniently prepared as shown in Scheme III.

[0151] Thus, a tricyclic diazepine of formula (6) is treated with anappropriately substituted acylating agent such as an aroyl halide,preferably an appropriately substituted acyl chloride or bromide offormula (7, J=COCl or COBr) wherein R₄ is ultimately chosen on the basisof its compatibility with the present reaction scheme, in the presenceof an inorganic base such as potassium carbonate, or in the presence ofan organic base such as pyridine, 4-(dimethylamino)pyridine, or atertiary amine such as triethylamine or N,N-diisopropylethyl amine, inan aprotic solvent such as dichloromethane, N,N-dimethylformamide ortetrahydrofuran, at temperatures ranging from −5° C. to 50° C. toprovide intermediates of general formula (I) wherein R₄ is definedhereinbefore.

[0152] Alternatively, the acylating species of formula (7) can be amixed anhydride of the corresponding carboxylic acid, such as thatprepared by treating said acid with 2,4,6-trichlorobenzoyl chloride, inan aprotic organic solvent such as dichloromethane, according to theprocedure of Inanaga et al., Bull. Chem. Soc. Jpn., 52, 1989 (1979).

[0153] Treatment of said mixed anhydride of general formula (7) with atricyclic diazepine of formula (6) in a solvent such as dichloromethane,and in the presence of an organic base such as4-(dimethylamino)pyridine, at temperatures ranging from 0° C. to thereflux temperature of the solvent, yields the intermediate acylatedderivative (1) of Scheme III.

[0154] The acylating intermediate of formula (7) is ultimately chosen onthe basis of its compatibility with the R₄ groups, and its reactivitywith the tricyclic diazepine of formula (6).

[0155] The desired intermediates of formula (7) of Scheme III wherein R₄consists of the moiety B-C wherein B is (a) and C is (c) can beconveniently prepared by a process shown in Scheme IV. Thus, anappropriately substituted aryl(heteroaryl) iodide (bromide, chloride ortrifluoromethane sulfonate) of formula (8, wherein P is a carboxylicacid protecting group, preferably P=alkyl or benzyl, M=I, Br, Cl, OTf)wherein A, R₅, R₆ and R₇ are defined hereinbefore, is reacted with anaryl(heteroaryl) tri(alkyl)tin(IV) derivative of formula (9,W=Sn(trialkyl)₃, preferably Sn(n-Bu)₃) wherein A, R₈, R₉ and R₁₀ aredefined hereinbefore, in the presence of a Pd(0) catalyst, in thepresence or absence of inorganic salts (e.g. LiCl), to provide theintermediate ester (10). Subsequent unmasking of the carboxylic acid byhydrolysis, hydrogenolysis or similar methods known in the art, followedby activation of the intermediate acid (11) provides the desiredcompounds of formula (19) wherein A, R₅, R₆, R₇, R₈, R₉ and R₁₀ arehereinbefore defined, suitable for coupling with the tricyclic diazepineof formula (6).

[0156] The desired intermediates of formula (7) of Scheme III wherein R₄consists of the moiety B-C where B is (a) and C is (d), (e) or B is (b)and C is either (c), (d), (e) or (f) can be prepared by a processanalogous to that exemplified in Scheme IV by replacing intermediates offormula (8 and 9) with appropriately substituted naphthyl, quinolyl,pyrimidinyl or pyrazinyl intermediates.

[0157] Alternatively, the desired intermediates of formula (10) ofScheme IV wherein R₄ consists of the moiety B-C where B is (a) and C is(c) can be prepared by Suzuki coupling from the iodide(bromide,chloride, trifluoromethanesulfonate) (8, M=I, Br, Cl or OTf) and anappropriately substituted aryl(heteroaryl) boron derivative of formula(9, preferably W=B(OH)₂) in the presence of a palladium catalyst such aspalladium(ll) acetate or tetrakis(triphenylphosphine) palladium(0), andan organic base such as triethylamine or an inorganic base such assodium(potassium or cesium) carbonate with or without addedtetrabutylammonium bromide(iodide), in a mixture of solvents such astoluene-ethanol-water, acetone-water, water or water-acetonitrile attemperatures ranging from ambient to the reflux temperature of thesolvent (Suzuki, Pure & Appl. Chem. 66, 213-222 (1994); Badone et al.,J. Org. Chem. 62, 7170-7173 (1997); Wolfe et al., J. Am. Chem. Soc. 121,9559 (1999); Shen, Tetr. Letters 38, 5575 (1997)). The exact conditionsfor the Suzuki coupling of the halide and the boronic acid intermediatesare chosen on the basis of the nature of the substrate and thesubstituents. Alternatively, the coupling of (8, M=I or Br) with (9,A═N) can be carried out by using a dialkylborane, preferably adiethylpyridoborane in the presence of an inorganic base such aspotassium hydroxide and tetrabutylammonium bromide(iodide) in an aproticsolvent such as tetrahydrofuran, according to the method of Ishikura etal., Synthesis 936-938 (1984). The desired intermediates of formula (10)of Scheme IV can be similarly prepared from the bromide (8, M=Br) andthe boronic acid (9) in a solvent such as dioxane in the presence ofpotassium phosphate and a Pd(0) catalyst. Alternatively, a crosscoupling reaction of an iodide (bromide, or trifluoromethane sulfonate)of formula (9, W=Br, I, OTf) with a bis(pinacolato)diboron [boronicacid, or trialkyltin(IV)] derivative of formula (8, M=

[0158] B(OH)₂, or SnBu₃) yields the desired intermediate of formula (10)which is converted to (I) in the manner of Scheme IV.

[0159] The desired intermediates of formula (10) of Scheme IV wherein R₄consists of the moiety B-C wherein B is (a) and C is (d), (e) or (f), orB is (b) and C is either (c), (d), (e) or (f) can be prepared inanalogous fashion by replacing intermediates of formulas (8 and 9) withappropriately substituted naphthyl, quinolyl, pyrimidinyl or pyrazinylintermediates.

[0160] The required appropriately substituted aryl(heteroaryl) halidesof formula (8, M=Br or I) of Scheme IV are either availablecommercially, or are known in the art or can be readily accessed inquantitative yields and high purity by diazotization of thecorresponding substituted anilines (8, P═H, alkyl or benzyl, M=NH₂)followed by reaction of the intermediate diazonium salt with iodine andpotassium iodide in aqueous acidic medium essentially according to theprocedures of Street et al,. J. Med. Chem. 36, 1529 (1993) and Coffen etal., J. Org. Chem. 49, 296 (1984) or with copper(I) bromide,respectively (March, Advanced Organic Chemistry, 3^(rd) Edn., p.647-648,John Wiley & Sons, New York (1985)).

[0161] Alternatively, the desired intermediates of formula (11, A═CH) ofScheme IV wherein R₄ consists of the moiety B-C wherein B is (a, A═CH)and C is (c, A═CH) can be conveniently prepared as shown in Scheme V bycross-coupling reaction of an appropriately substituted pinacolatoborane of formula (13, A═CH) wherein R₈, R₉ and R₁₀ are hereinbeforedefined, with an aryl triflate of formula (14, Y═OTf) or an aryl halide(14, Y=Br, I) wherein R₅, R₆ and R₇ are defined hereinbefore, accordingto the general procedures of lshiyama et al., Tetr. Lett. 38, 3447-3450(1997) and Giroux et al. Tetr. Lett. 38, 3841-3844 (1997), followed bybasic or acidic hydrolysis of the intermediate nitrile of formula (15)(cf. March, Advanced Organic Chemistry, 3rd Edn., John Wiley & Sons, NewYork, p. 788 (1985)).

[0162] Alternatively, reaction of an iodide (bromide, ortrifluoromethanesulfonate) of formula (12, X=Br, I, or Tf) with abis(pinacolato)diboron [boronic acid or trialkyl tin(IV)] derivative offormula (14, Y=

[0163] B(OH)₂, or SnBu₃) yields the desired intermediate of formula (15)which is converted to (6) in the manner of Scheme V.

[0164] The desired intermediates of formula (11) of Scheme IV can beprepared in analogous fashion by replacing intermediates of formulas (13and 14) with appropriately substituted naphthyl intermediates.

[0165] The desired phenyl boronic esters of formula (13) of Scheme V canbe conveniently prepared by the palladium-catalyzed cross-couplingreaction of the pinacol ester of diboronic acid (16) with anappropriately substituted aryl halide preferably a bromide or iodide(12, X=Br, I) or aryl triflate (12, X═OTf) according to the describedprocedures of Ishiyama et al., J. Org. Chem. 60, 7508-7510 (1995) andGiroux et al., Tetr. Lett. 38, 3841-3844 (1997).

[0166] The desired compounds of formula (I) of Scheme IV wherein R₄consists of the moiety B-C wherein B is (a) and C is (c) can bealternatively prepared by a process shown in Scheme VI.

[0167] Thus, a tricyclic diazepine of formula (6) is treated with anappropriately substituted acylating agent such as a haloaroyl(heteroaroyl)halide, preferably an iodo(bromo) aroyl(heteroaroyl)chloride(bromide) of formula (17, J=COCl or COBr; X=I, Br) wherein R₅,R₆ and R₇ are hereinbefore defined using any of the procedureshereinbefore described, to provide the acylated intermediate of generalformula (18) of Scheme VI.

[0168] Alternatively, the acylating species of formula (17) can be amixed anhydride of the corresponding carboxylic acid. Treatment of saidmixed anhydride of general formula (17) with a tricyclic diazepine offormula (6) according to the procedure described hereinbefore yields theintermediate acylated derivative (18).

[0169] The acylating intermediate of formula (17) is ultimately chosenon the basis of its compatibility with A and the R₅, R₆ and R₇ groups,and its reactivity with the tricyclic diazepine of formula (6).

[0170] A Stille coupling reaction of (18, X═I) with an appropriatelysubstituted organotin reagent such as a trialkyltin(IV) derivative,preferably a tri-n-butyltin(IV) derivative of formula (9, W=SnBu₃) whereA, R₈, R₉ and R₁₀ are hereinbefore defined, in the presence of acatalyst such as tetrakis (triphenylphosphine) palladium (0), in anaprotic organic solvent such as toluene and N,N-dimethylformamide, attemperatures ranging from ambient to 150° C. (cf. Farina et al., J. Org.Chem, 59, 5905 (1994) and references cited therein) affords the desiredcompounds of formula (I) wherein

[0171] A, R₃, R₅, R₆, R₇, R, R₉ and R₁₀ are as defined hereinbefore.

[0172] Alternatively, reaction of a compound of formula (18, X=Cl, Bror 1) with an appropriately substituted aryl(heteroaryl) boronic acid offormula (9, W=B(OH)₂) wherein A, R₅, R₆, R₇, R₈, R₉ and R₁₀ arehereinbefore defined, in a mixture of solvents such astoluene-ethanol-water, and in the presence of a Pd(0) catalys, and abase such as sodium carbonate, at temperatures ranging from ambient tothe reflux temperature of the solvent, yields the desired compounds offormula (I) wherein

[0173] A, R₃, R₅, R₆, R₇, R₈, R₉ and R₁₀ are as defined hereinbefore.

[0174] The preferred substituted aroyl(heteroaroyl) chlorides(bromides)of formula (17) of Scheme VI(X═I, Br; J=COCl or COBr) wherein A, R₅, R₆and R₇ are as defined hereinbefore, are either available commercially,or are known in the art, or can be readily prepared by proceduresanalogous to those in the literature for the known compounds.

[0175] The intermediates of formula (9, W=Sn(alkyl)₃, alkyl=n-butyl) ofScheme VI are either commercially available, or can be convenientlyprepared as shown in Scheme VII from the corresponding bromo startingmaterials of formula (20) wherein A, R₈, R₉, and R₁₀ are hereinbeforedefined, by first reacting them with n-butyl lithium followed byreaction of the intermediate lithiated species with a trialkyl(preferably trimethyl or tri-n-butyl)tin(IV) chloride to give thedesired stannane of formula (9, alkyl =n-butyl) wherein R₈, R₉, and R₁₀are as defined hereinbefore.

[0176] The preferred substituted aryl(heteroaryl) boronic acids offormula (9, W=B(OH)₂) are either available commercially, or are known inthe art, or can be readily prepared by procedures analogous to those inthe literature for the known compounds.

[0177] The desired compounds of formula (I) of Scheme VI wherein R₄consists of the moiety B-C wherein B is (a) and C is (d), (e) or (f), orB is (b) and C is either (c), (d), (e) or (f) can be prepared inanalogous fashion by replacing intermediates of formulas (17 and 9) withappropriately substituted naphthyl, quinolyl, pyrimidinyl or pyrazinylintermediates.

[0178] Alternatively, as shown in Scheme VIII, the appropriatelysubstituted aroyl(heteroaroyl) halides, preferably aroyl(heteroaroyl)chlorides of formula (21, J=COCl) where A, R₅, R₆ and R₇ arehereinbefore defined, are reacted with a tricyclic diazepine of formula(6) to provide the intermediate bromides of formula (22). Subsequentreaction of (22) with an hexa alkyl-di-tin (preferablyhexa-n-butyl-di-tin(IV)) in the presence of a Pd(0) catalyst such astetrakis(tri-phenylphosphine)palladium(0) and lithium chloride, providesthe stannane intermediate of formula (23). Further reaction of thetri-n-butyl tin(IV) derivative (23) with the appropriately substitutedaryl(heteroaryl) halide of formula (24, M =Br, I) wherein A, R₈, R₉, andR₁₀ are hereinbefore defined, in the presence of a Pd(0) catalyst suchas tetrakis(triphenylphosphine) palladium(0), yields the desiredcompounds of formula (I) wherein R₄ consists of the moiety B-C wherein Bis (a) and C is (c), and

[0179] A, R₅, R₆, R₇, R₈, R₉ and R₁₀ are defined hereinbefore.

[0180] The desired compounds of formula (I) of Scheme VIII wherein R₄consists of the moiety B-C wherein B is (a) or (b), and C is (d), (e) or(f) can be prepared in analogous fashion by replacing intermediates offormulas (21 and 24) with appropriately substituted naphthyl, quinolyl,pyrimidinyl or pyrazinyl intermediates.

[0181] Alternatively, the desired compounds of formula (I) of SchemeVIII wherein R₄ consists of the moiety B-C wherein B is (a, A═CH), and Cis (c, A═CH) can be prepared as shown in Scheme IX.

[0182] Thus, an appropriately substituted biphenyl of formula (43)wherein R₅, R₆, R₇, R₈, R₉ and R₁₀ are defined hereinbefore, is treatedwith carbon monoxide in the presence of a tricyclic diazepine of formula(6), a palladium(0) catalyst preferably PdBr₂(Ph₃P)₂, and a tertiaryamine preferably n-tributylamin, in a solvent such as anisole or dioxaneat temperatures ranging from ambient to the reflux temperature of thesolvent (cf. Schoenberg et al., J. Org. Chem. 39, 3327 (1974)), toprovide the desired compounds of formula (I) wherein A is CH, and

[0183] R₃, R₅, R₆, R₇, R₈, R₉ and R₁₀ are defined hereinbefore.

[0184] In analogous fashion one can prepare compounds of formula (I) ofScheme IX wherein R₄ consists of the moiety B-C wherein B is (b) and Cis (c, A═CH) or (d, A═CH) provided that the intermediates of formula(43) are replaced by the appropriately substituted phenyl or naphthylintermediates.

[0185] A preferred process for the preparation of the compounds offormula (I) of Scheme I wherein

[0186] A, R₃, R₅, R₆ and R₇ are defined hereinbefore, and R₄ consists ofthe moiety B-C wherein B is (a) and C is (g) defined hereinbefore, isshown in Scheme X.

[0187] Thus, an appropriately substituted aroyl(heteroaroyl) halidepreferably an aroyl(heteroaroyl) chloride, of formula (25, J=COCl) isreacted with a tricyclic diazepine of formula (6), in the presence of abase such as pyridine, or a tertiary amine such as triethylamine orN,N-diisopropylethylamine, in an aprotic organic solvent such asdichloromethane or tetrahydrofuran, at temperatures from −40° C. to 50°C. to provide the acylated intermediate of formula (26). Alternatively,the acylating species can be a mixed anhydride under the reactionconditions described hereinbefore. Subsequent reduction of (26) ispreferably effected under conditions of catalytic reduction (i.e.hydrogen, Pd on charcoal), transfer hydrogenation (i.e.hydrazine/ethanol/Pd on charcoal) or under chemical reduction conditions(i.e. with tin(II)chloride dihydrate in a protic organic solvent such asethanol, or zinc in acetic acid) or related reduction conditions knownin the art, to yield the desired aniline of formula (27). The exactconditions for the conversion of the nitro to amino group are chosen onthe basis of compatibility with the preservation of other functionalgroups in the molecule. Condensation of (27) with a 1,4-diketone offormula (28) in an aprotic organic solvent such as benzene or toluene inthe presence of acetic acid or a catalytic amount of paratoluenesulfonicacid with concomitant removal of water at temperatures ranging fromambient to reflux temperature of the solvent according to the generalprocedure of Bruekelman et al., J. Chem. Soc. Perkin Trans. 1,2801-2807(1984), provides the desired compounds of formula (I) wherein R₄consists of the moiety B-C wherein B is (a) and C is (g), and

[0188] A, R₃, R₅, R₆, R₇, R₁₁ and R₁₂ are defined hereinbefore.

[0189] The desired compounds of formula (I) of Scheme X wherein R₄consists of the moiety B-C wherein B is (b) and C is (g) can be preparedin analogous fashion by replacing the intermediate of formula (25) withan appropriately substituted naphthyl.

[0190] Alternatively, the desired compounds of formula (I) of Scheme Xcan be prepared as shown in Scheme XI.

[0191] According to this process an aryl(heteroaryl) nitrile of formula(29) is condensed with a 1,4-diketone of formula (28), in an aproticorganic solvent such as benzene or toluene, in the presence of aceticacid or a catalytic amount of paratoluenesulfonic acid with concomitantremoval of water, at temperatures ranging from ambient to refluxtemperature of the solvent according to the general procedure ofBruekelman et al., J. Chem. Soc. Perkin Trans. 1, 2801-2807 (1984), toyield the intermediate pyrrole of formula (30). Subsequent hydrolysis ofthe nitrile (30) to the carboxylic acid of formula (31) is efficientlyaccomplished by treatment of (30) with aqueous base (cf. March, AdvancedOrganic Chemistry, 3d Edn., John Wiley & Sons, New York, p. 788 (1985)).Subsequent conversion of the acid (31) into an acylating species,preferably an acid chloride(bromide) of formula (32, J=COCl or COBr) ora mixed anhydride is accomplished by procedures analogous to thosedescribed hereinbefore. The acylating agent (32) is used to acylate atricyclic diazepine of formula (6) to provide the desired compounds offormula (I) wherein

[0192] A and R₃ are defined hereinbefore, and R₄ consists of the moietyB-C wherein B is (a) and C is the moiety (g) defined hereinbefore.

[0193] The compounds of formula (I) of Scheme XI wherein R₄ consists ofthe moiety B-C wherein B is (b) and C is (g) defined hereinbefore, canbe prepared in analogous fashion by replacing the intermediates offormula (29) with an appropriately substituted naphthyl.

[0194] A preferred process for the preparation of the desired compoundsof general formula (I) of Scheme I wherein R₄ consists of the moietyB-C, where B is selected from the group (a) and C is selected from thegroup (g) defined hereinbefore is shown in Scheme XII.

[0195] Thus, a tricyclic diazepine of formula (33) wherein

[0196] and R₃ are before, carrying a protecting group such as afluorenylalkoxycarbonyl bly a fluorenylmethyloxycarbonyl (P=Fmoc) group,or an alkoxycarbonyl up preferably a tert-butyloxycarbonyl (P=Boc) groupis reacted with a l halide preferably trichloroacetyl chloride, in thepresence of an organic N,N-diisopropylethyl amine (Hunig's base) or atertiary amine such as optionally in the presence of catalytic amountsof 4-pyridine, in an aprotic organic solvent such as dichloromethane, atranging from −10° C. to ambient to provide the desired trichloroacetylintermediate of formula (34). Subsequent hydrolysis of thetrichloroacetyl group with aqueous base such as sodium hydroxide, in anorganic solvent such as acetone, at temperatures ranging from −10° C. toambient, is accompanied by simultaneous removal of the protecting groupand yields the intermediate acid of formula (35). The required amidationof the carboxylic acid (35) can be effectively accomplished by treating(35) with an activating reagent such as N,N-dicyclohexyl carbodiimide or1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride in thepresence of 1-hydroxybenzotriazole, followed by reaction of theactivated intermediate with an appropriately substituted primary orsecondary amine of formula (5) preferably in the presence of Hünig'sbase or a catalytic amount of 4-(dimethylamino)pyridine in an aproticsolvent such as dichloromethane, N,N-dimethylformamide ortetrahydrofuran, at temperatures ranging from −10° C. to ambient.

[0197] Other coupling reagents known in the literature that have beenused in the formation of amide bonds in peptide synthesis can also beused for the preparation of compounds of formula (36) wherein

[0198] R and R₃ are as defined hereinbefore. The method of choice forthe preparation of compounds of formula (36) from the intermediatecarboxylic acid (35) is ultimately chosen on the basis of itscompatibility with the

[0199] and R₃ groups, and its reactivity with the tricyclic diazepine offormula (6). Subsequent reaction of a tricyclic diazepine amide (36)with an acylating agent of formula (32) of Scheme XI provides thedesired compounds of formula (I) wherein

[0200] A and R₃ are defined hereinbefore, R₄ consists of the moiety B-Cwherein B is (a) and C is the moiety (g) defined hereinbefore.

[0201] The preferred compounds of formula (I) of Scheme I wherein R₄consists of the moiety B-C wherein B is (b) and C is the moiety (g)defined hereinbefore, can be prepared in analogous fashion by replacingthe intermediate of formula (32) of Scheme XII with an appropriatelysubstituted naphthyl intermediate.

[0202] Preferred processes for the preparation of compounds of formula(I) of Scheme I wherein R₄ consists of the moiety B-C wherein B is (a)or (b) and C is (d), (e) or (f) and

[0203] A, R, R₃, R₅, R₆, R₇, R₈, R₉, and R₁₀ are defined hereinbefore,also utilize acylation of the amide intermediate (36) of Scheme XII withan acylating agent of formula (19) of Scheme IV.

[0204] An alternate preferred process for the preparation of thecompounds of formula (I) of Scheme I wherein R₄ consists of the moietyB-C wherein B is (a) and C is (g) defined hereinbefore, is shown inScheme XIII.

[0205] According to the above process a substituted tricyclic diazepineof formula (37) wherein

[0206] A, R₃, R₅, R₆ and R₇ are defined hereinbefore, carrying aprotecting group such as a fluorenylalkoxycarbonyl group, preferably afluorenylmethyloxycarbonyl (P=Fmoc) group is reacted with aperhaloalkanoyl halide preferably trichloroacetyl chloride, in thepresence of an organic base such as N,N-diisopropylethyl amine (Hunig'sbase) or a tertiary amine such as triethylamine, in an aprotic organicsolvent such as dichloromethane, at temperatures ranging from −10° C. toambient, to provide the desired trichloroacetyl intermediate of formula(38). Subsequent deprotection of (38) is carried out by treatment with asolution of an organic base preferably piperidine, in an organic solventsuch as N,N-dimethylformamide at ambient temperature to provide thedesired aniline (44). Condensation of (44) with a 1,4-diketone offormula (28) either neat or in an aprotic organic solvent such asbenzene or toluene, in the presence of a catalytic amount of acarboxylic acid preferably para-toluenesulfonic acid or acetic acid,with concomitant removal of water, at temperatures ranging from ambientto 100° C. or to the reflux temperature of the solvent according to thegeneral procedure of Bruekelman et al., J. Chem. Soc. Perkin Trans.I,2801-2807 (1984) provides the desired intermediate of formula (45).Subsequent hydrolysis of the trichloroacetyl group with aqueous basesuch as sodium hydroxide, in an organic solvent such as acetone ortetrahydrofuran, at temperatures ranging from −10° C. to the refluxtemperature of the solvent, yields the intermediate carboxylic acid offormula (46). Subsequent amidation provides the desired compounds offormula (I) wherein R₄ consists of the moiety B-C wherein B is (a) and Cis (g), and

[0207] A, R₃, R₅, R₆, R₇, R₁₁ and R₁₂ are defined hereinbefore,

[0208] The required amidation of (46) can be effectively accomplished bytreating said carboxylic acid with an activating reagent such asN,N-dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride in the presence of 1-hydroxybenzotriazole,followed by reaction of the activated intermediate with an appropriatelysubstituted primary or secondary amine of formula (5) preferably in thepresence of Hünig's base or a catalytic amount of4-(dimethylamino)pyridine in an aprotic solvent such as dichloromethane,N,N-dimethylformamide or tetrahydrofuran, at temperatures ranging from−10° C. to ambient. Other coupling reagents known in the literature thathave been used in the formation of amide bonds in peptide synthesis canalso be used for the preparation of compounds of formula (I) wherein R₄consists of the moiety B-C wherein B is (a) and C is (g), and

[0209] A, R₃, R₅, R₆, R₇, R₁₁ and R₁₂ are defined hereinbefore. Themethod of choice for the preparation of compounds of formula (I) fromthe intermediate carboxylic acid (465) is ultimately chosen on the basisof its compatibility with the

[0210] and R₃ groups, and its reactivity with the tricyclic diazepine offormula (6).

[0211] The desired compounds of formula (I) of Scheme XIII wherein R₄consists of the moiety B-C wherein B is (b) and C is (g) can be preparedin analogous fashion by replacing the intermediate of formula (27) withan appropriately substituted naphthyl intermediate.

[0212] Alternatively, the intermediate acids of formula (35) of SchemeXII wherein

[0213] and R₃ are defined hereinbefore, can be obtained by reacting atricyclic diazepine of formula (6) with an excess of an acylating agentpreferably trifluoroacetic anhydride or trichloroacetyl chloride, in thepresence of an inorganic base such as potassium carbonate or an organicbase such as N,N-diisopropylethylamin, in an aprotic solvent such asN,N-dimethylformamide, followed by basic hydrolysis of the intermediatebis-trifluoroacetyl (trichloroacetyl) intermediate of formula (39, X═For Cl) preferably with aqueous sodium hydroxide, in a protic organicsolvent such as ethanol, at temperatures ranging from ambient to thereflux temperature of the solvent as exemplified in Scheme XIV.

[0214] Preferred processes for the preparation of compounds of formula(I) of Scheme I wherein R₄ consists of the moiety B-C wherein B is (a)or (b) and C is (d), (e) or (f) and

[0215] A, R, R₃, R₅, R₆, R₇, R₈, R₉, and R₁₀ are defined hereinbefore,also utilize acylation of the amide intermediate (36) of Scheme XII withan acylating agent of formula (17) of Scheme IV, as shown in Scheme XV.

[0216] Alternatively, the preferred compounds of formula (I) of Scheme Iwherein R₄ consists of the moiety B-C wherein B is (a) and C is (c) and

[0217] A, R, R₃, R₅, R₆, R₇, R₈, R₉, and R₁₀ are defined hereinbefore,can be prepared by acylation of the amide intermediate (36) of SchemeXII with an acylating agent of formula (21) of Scheme VIII, as shown inScheme XVI.

[0218] Alternatively, the preferred compounds of formula (I) of Scheme(I) wherein R₄ consists of the moiety B-C wherein B is (a) and C is (c)and

[0219] A, R, R₃, R₅, R₆, R₇, R₈, R₉, and R₁₀ are defined hereinbefore,can be prepared by acylation of the amide intermediate (36) of SchemeXII with an acylating agent of formula (19) of Scheme IV, wherein J ishereinbefore defined, as shown in Scheme XVII.

[0220] A preferred process for the preparation of compounds of formula(6) of Scheme R₁ III wherein

[0221] and R₄ consists of the moiety B-C wherein B is (a) or (b) and Cis (d), (e) or (f), R₃ is hydrogen, and A, R, R₅, R₆, R₇, R₈, R₉, andR₁₀ are defined hereinbefore, is shown in Scheme XVIII.

[0222] Thus, an appropriately substituted chloro(bromo)methylpyridine offormula (47, wherein X=Cl or Br, and P is a carboxylic acid protectinggroup, preferably P=alkyl), is condensed with a pyrrolo carboxaldehydeof formula (48, R₃=hydrogen) in the presence of an inorganic base,preferably sodium hydride, in an aprotic organic solvent, preferablyN,N-dimethylformamide, at temperatures ranging from −10° C. to ambient,to yield the pyrrole derivative of formula (49, R₃=H). Subsequent basichydrolysis of the ester (49) followed by Curtius rearrangement of theintermediate according to the general procedure of Kamikawa et al.,Biorg. Med. Chem. 4, 1317 (1996) provides the benzylcarbamate of formula(50, R₃=H). Hydrogenation of (50) in an aprotic organic solvent such asethyl acetate, in the presence of palladium-on-charcoal and a traceamount of an organic acid provides the tricyclic pyridodiazepine offormula (6, R₃═H) of Scheme III.

[0223] The subject compounds of the present invention were tested forbiological activity according to the following procedures.

[0224] Vasopressin Binding in Chinese Hamster Ovary Cell MembranesExpressing Human Vasopressin V1a Subtype Receptors

[0225] Receptor source:

[0226] Chinese hamster ovary cells (CHO cells) stably transfected withthe human vasopressin V_(1a) subtype receptors were either obtained fromBioSignal Inc., 1744 rue Williams, Montreal, Quebec, Canada or obtainedfrom M. Thibonnier, Case Western Reserve University School of Medicine,Cleveland, Ohio.

[0227] A. Passaging and Amplification of Cells:

[0228] CHO cells transfected with the human vasopressin V_(1a) subtypereceptors obtained from M. Thibonnier (pZeoSV vector) are allowed togrow to confluency (approx. >90%) in T-150 flasks under sterileconditions, in a cell culture medium of F-12 Nutrient Mixture (HAM) withL-glutamine (Gibco Cat. #11765-054) containing 15 mM HEPES (Gibco Cat.#15630-080), 1% antibiotic/antimycotic (add 5 mL 100×, Gibco Cat.#15240-062 per 500 mL F-12), 250 μg/mL Zeocin (add 1.25 mL of 100 mg/mLInvitrogen R-250-01 per 500 mL F-12) and 10% Fetal Bovine Serum(Qualified, heat inactivated, Gibco Cat. #16140-063). The medium isremoved by aspiration and the cells are washed with 10 mL of Hank'sBalanced Salt solution (Gibco Cat. #14175-095). The salt solution isremoved by aspiration and the cells are trypsinized with 5 mL oftrypsin-EDTA (0.05% trypsin, 0.53 mM EDTA-4Na, Gibco Cat. #25300-070)for 1 min. The trypsin is removed by aspiration and the cells dislodgedby tapping. Cell Culture medium (e.g. 30 mL for 1:30 split) isimmediately added and mixed well to inactivate trypsin. 1 mL of detachedcells is added to new culture flasks containing fresh cell culturemedium (e.g., into 25 mL per T-1 50 flask), and mixed gently. The cellsare incubated at 37° C. in 5% CO₂. The medium is changed at 3 to 4 daysinterval (or as appropriate). The cells grow to confluency(approx. >75%-95%) within 7-8 days. All steps are done under sterileconditions.

[0229] B. Membrane Preparation:

[0230] The cells are washed twice gently with Hank's Balanced Saltsolution (e.g,. use 10 mL per T-150 flask). The excess is removed andthe cells are bathed for 15-30 min. in an enzyme-free Cell DissociationBuffer (e.g. use 8 mL Hank's Based, Gibco Cat. #13150-016 per T-150flask) until the cells are loosened. The contents are transferred tocentrifuge tubes (50 mL) kept in an ice bath. All subsequent steps aredone at 4° C. The tubes are centrifuged at 300× g for 15 min (1380 rpmon SORVAL, Model RT6000D, using the rotor for 50 mL tubes). Thesupernatant is discarded and the cells suspended in homogenizingbuffer(10 mM Tris-HCl containing 0.25 M sucrose and 1 mM EDTA, pH 7.4)ensuring that the volume of the buffer is about ten times the volume ofthe cell pellet. The cells are pooled into a centrifuge tube (50 mL) andhomogenized with Polytron at setting 6 for 10 sec. The homogenate istransferred into a Potter-Elvjehm homogenizer and homogenized with 3strokes. The homogenate is centrifuged at 1500× g for 10 min at 4° C.(3100 rpm using SORVAL, model RT6000D, using the rotor for 50 mL tubes).The pellet is discarded. The supernatant is centrifuged at 100,000 x gfor 60 min. at 4° C. (Beckman L8-80M ultracentrifuge; spin at 37,500 rpmwith rotor type 70 Ti for 50 mL tubes; 38,000 rpm with type 80Ti for 15mL tubes; or 35,800 rpm with rotor type 45Ti). The supernantant isdiscarded and the pellet suspended in 3 to 4 mL of Tris buffer (50 mMTRIS—HCl, pH 7.4). The protein content is estimated by the Bradford orLowry method. The volume of the membrane suspension is adjusted with themembrane buffer (50 mM Tris-HCl containing 0.1% BSA and 0.1 mM PMSF) togive 3.0 mg/mL (or as appropriate) of protein. The membranes arealiquoted and stored at −70° C.

[0231] C. Radioligand Binding Assay:

[0232] In wells of a 96-well format microtiter plate, is added 90, 110or 130 μL (to make up a final volume of 200 μL) of assay buffercontaining 50 mM of Tris-HCl (pH 7.4), BSA (heat inactivated,protease-free), 0.1% of 5 mM MgCl₂, 1 mg % aprotinin, 1 mg % leupeptin,2 mg % 1,10-phenanthroline, 10 mg % trypsin inhibitor, and 0.1 mM PMSF.The inhibitors are added on the day of the experiment. The componentsare mixed at room temperature, and then kept in ice bath followingadjustment of the pH to 7.4. To each well is added 20 pL of unlabeledManning ligand (to give a final concentration of 0.1 to 10 nM forstandard curve and 1000 nM for non specific binding) or test compoundsin 50% DMSO (e.g. for final concentrations of 0.1 to 1000 nM or asappropriate) or 50% DMSO as vehicle control. 20 μL of 50% DMSO is addedfor Manning and other peptide ligands and the assay buffer volume isadjusted accordingly. To each well is added 50 μL of frozen membranesuspension thawed immediately prior to use and diluted in the assaybuffer to the required concentration (equivalent to 25 to 50 μg ofprotein/well as needed). 20 μL of 8 nM [³H]Manning ligand in the assaybuffer, prepared just before use, is added, and incubated at roomtemperature for 60 min. shaking the plate on a mechanical shaker for thefirst 15 min. The incubation is stopped by rapid filtration of the theplate contents followed by wash with ice-cold buffer (50 mM Tris-HCl, pH7.4) using a cell harvester (Tomtek and Printed filtermat-B filterpaper). The filter paper is thoroughly dried (7-12 min. in a microwaveoven) and impregnated with MeltiLex B/H melt-on scintillation wax sheetsand the radioactivity counted in a betaplate scintillation counter.

[0233] Vasopressin Binding in Chinese Hamster Ovary Cell MembranesExpressing Human Vasopressin V₂ Subtype Receptors

[0234] Receptor Source:

[0235] Chinese Hamster Ovary (CHO) cells stably transfected with thehuman V₂ subtype receptors were obtained from M. Thibonnier, CaseWestern Reserve University School of Medicine, Cleveland, Ohio.

[0236] A. Passaging and Amplification of Cells:

[0237] CHO cells transfected with the human vasopressin V₂ subtypereceptors obtained from M. Thibonnier (pZeoSV vector) are allowed togrow to confluency (approx. >90%) in T-150 flasks under sterileconditions, in a cell culture medium ofF-12 Nutrient Mixture (HAM) withL-glutamine (Gibco Cat. #11765-054) containing 15 mM HEPES (Gibco Cat.#15630-080), 1% antibiotic/antimycotic (add 5 mL 100×, Gibco Cat.#15240-062 per 500 mL F-12), 250 μg/mL Zeocin (add 1.25 mL of 100 mg/mLInvitrogen R-250-01 per 500 mL F-1 2) and 10% Fetal Bovine Serum(Qualified, heat inactivated, Gibco Cat. #16140-063). The medium isremoved by aspiration and the cells washed with 10 mL of Hank's BalancedSalt solution (Gibco Cat. #14175-095). The salt solution is removed byaspiration and the cells trypsinized with 5 mL of trypsin-EDTA (0.05%trypsin, 0.53 mM EDTA-4Na, Gibco Cat. #25300-070) for 1 min. The trypsinis removed by aspiration and the cells dislodged by tapping. CellCulture medium (e.g. 30 mL for 1:30 split) is immediately added andmixed well to inactivate trypsin. 1 mL of detached cells is added to newculture flasks containing fresh Cell Culture medium (e.g. into 25 mL perT-150 flask), and mixed gently. The cells are incubated at 37° C. in 5%CO₂. The medium is changed at 3 to 4 day interval (or as appropriate).The cells grow to confluency (approx. >75%-95%) within 7-8 days. Allsteps are done under sterile conditions.

[0238] B. Membrane Preparation:

[0239] The cells are washed twice gently with Hank's Balanced Saltsolution (e.g. use 10 mL per T-150 flask). The excess solution isremoved and the cells bathed for 15-30 min. in an enzyme-free CellDissociation Buffer (e.g. use 8 mL Hank's Based, Gibco Cat. # 13150-016per T-150 flask) until cells are loosened. The contents are transferredto centrifuge tubes (50 mL) kept in ice bath. All subsequent steps aredone at 4° C. The tubes are centrifuged at 300× g for 15 min (1380 rpmon SORVAL, Model RT6000D, using the rotor for 50 mL tubes). Thesupernatant is discarded and the cells suspended in homogenizing buffer(10 mM Tris-HCl containing 0.25 M sucrose and 1 mM EDTA, pH 7.4)ensuring that the volume of the buffer is about ten times the volume ofthe cell pellet. The cells are pooled into a centrifuge tube (50 mL) andhomogenized with Polytron at setting 6 for 10 sec. The homogenate istransferred into a Potter-Elvjehm homogenizer and homogenized with 3strokes. The homogenate is centrifuged at 1500× g for 60 min at 4° C.(3100 rpm using SORVAL, model RT6000D, using the rotor for 50 mL tubes).The pellet is discarded. The supernatant is centrifuged at 100,000× gfor 60 min. at 4° C. (Beckman L8-80M ultracentrifuge; spin at 37,500 rpmwith rotor type 70 Ti for 50 mL tubes; 38,000 rpm with type 80Ti for 15mL tubes; or 35,800 rpm with rotor type 45Ti). The supernantant isdiscarded and the pellet suspended in 3 to 4 mL of Tris buffer (50 mMTRIS—HCl, pH 7.4). The protein content is estimated by the Bradford orLowry method. The volume of the membrane suspension is adjusted with themembrane buffer (50 mM Tris-HCl containing 0.1% BSA and 0.1 mM PMSF) togive 3.0 mg/mL (or as appropriate) of protein. The membranes arealiquoted and stored at −70. ° C.

[0240] C. Radioligand Binding Assay:

[0241] In wells of a 96-well format microtiter plate, is added 90, 110or 130 μL (to make up a final volume of 200 μL) of assay buffercontaining 50 mM of Tris-HCl (pH 7.4), BSA (heat inactivated,protease-free), 5 mM of 0.1% MgCl₂, 1 mg % aprotinin, 1 mg % leupeptin,2 mg % 1,10-phenanthroline, 10 mg % trypsin inhibitor, and 0.1 mM PMSF.The inhibitors are added on the day of the experiment. The componentsare mixed at room temperature, and then kept in ice bath followingadjustment of the pH to 7.4. To each well is added 20 1L of unlabeledarginine vasopressin (AVP) (to give a final concentration of 0.1 to. 10nM for standard curve and 1000 nM for non specific binding) or testcompounds in 50% DMSO (e.g. for final concentrations of 0.1 to 1000 nMor as appropriate) or 50% DMSO as vehicle control. For vasopressin andother peptide ligands 20 μL of 50% DMSO is added and the assay buffervolume is adjusted accordingly.

[0242] To each well is added 50 μL of frozen membrane suspension thawedimmediately prior to use and diluted in assay buffer to the requiredconcentration (equivalent to 25 to 50 μg of protein/well as needed). 20μL of 8 nM [³H]arginine vasopressin ligand in the assay buffer, preparedjust before use is added and incubated at room temperature for 60 min.shaking the plate on a mechanical shaker for the first 15 min. Theincubation is stopped by rapid filtration of the plate contents followedby wash with ice-cold buffer (50 mM Tris-HCl, pH 7.4) using a cellharvester (Tomtek and Printed filtermat-B filter paper). The filterpaper is thoroughly dried (7-12 min. in a microwave oven) andimpregnated with MeltiLex B/H melt-on scintillation wax sheets and theradioactivity counted in a betaplate scintillation counter.

[0243] Oxytocin Binding in Chinese Hamster Ovary Cell MembranesExpressing Human Oxytocin Receptors

[0244] Receptor Source:

[0245] Chinese Hamster Ovary (CHO) cells stably transfected with thehuman oxytocin receptor (cf. Tanizawa et al., U.S. Pat. No. 5,466,584(1995) to Rohto Pharmaceutical Co. Ltd., Osaka, Japan) were obtainedfrom M. Thibonnier, Case Western Reserve University School of Medicine,Cleveland, Ohio.

[0246] A. Passaging and Amplification of Cells:

[0247] CHO cells transfected with the human oxytocin receptors obtainedfrom M. Thibonnier (pcDNA3.1 vector) are allowed to grow to confluency(approx. >90%) in T-150 flasks under sterile conditions, in a cellculture medium of F-12 Nutrient Mixture (HAM) with L-glutamine (GibcoCat. #11765-054) containing 15 mM HEPES (Gibco Cat. #15630-080), 1%antibiotic/antimycotic (add 5 mL 100×, Gibco Cat. #15240-062 per 500 mLF-12), 400 μg/mL of Geneticin (add 4 mL of 50 mg/mL per 500 mL F-12) and10% Fetal Bovine Serum (Qualified, heat inactivated, Gibco Cat.#16140-063). The medium is removed by aspiration and the cells arewashed with 10 mL of Hank's Balanced Salt solution (Gibco Cat.#14175-095). The salt solution is removed by aspiration and the cellstrypsinized with 5 mL of trypsin-EDTA (0.05% trypsin, 0.53 mM EDTA-4Na,Gibco Cat. #25300-070) for 1 min. The trypsin is removed by aspirationand the cells dislodged by tapping. Cell Culture medium (e.g. 30 mL for1:30 split) is immediately added and mixed well to inactivate trypsin. 1mL of detached cells is added to new culture flasks containing freshCell Culture medium (e.g. into 25 mL per T-150 flask), and mixed gently.The cells are incubated at 37° C. in 5% CO₂. The medium is changed at 3to 4 days interval (or as appropriate). The cells grow to confluency(approx. >75%-95%) within 7-8 days. All steps are done under sterileconditions.

[0248] B. Membrane Preparation:

[0249] The cells are washed twice gently with Hank's Balanced Saltsolution (e.g., use 10 mL per T-1 50 flask). The excess solution isremoved and the cells bathed for 15-30 min. in an enzyme-free CellDissociation Buffer (e.g., use 8 mL Hank's Based, Gibco Cat. #13150-016per T-150 flask) until cells are loosened. The contents are transferredto centrifuge tubes (50 mL size) kept in ice bath. All subsequent stepsare done at 4° C. The tubes are centrifuged at 300× g for 15 min (1380rpm on SORVAL, Model RT6000D, using rotor for 50 mL tubes). Thesupernatant is discarded and the cells suspended in homogenizing buffer(10 mM Tris-HCl containing 0.25 M sucrose and 1 mM EDTA, pH 7.4)ensuring that the volume of the buffer is about ten times the volume ofthe cell pellet. The cells are pooled into a centrifuge tube (50 mL) andhomogenized with a Polytron at setting 6 for 10 sec. The homogenate istransferred into a Potter-Elvjehm homogenizer and homogenized with 3strokes. The homogenate is centrifuged at 1500× g for 10 min at 4° C.(3100 rpm using SORVAL, model RT6000D, using rotor for 50 mL tubes). Thepellet is discarded. The supernatant is centrifuged at 100,000× g for 60min. at 4° C. (Beckman L8-80M ultracentrifuge; spin at 37,500 rpm withrotor type 70 Ti for 50 mL tubes; 38,000 rpm with type 80Ti for 15 mLtubes; or 35,800 rpm with rotor type 45Ti). The supernantant isdiscarded and the pellet suspended in 3 to 4 mL of Tris buffer (50 mMTRIS—HCl, pH 7.4). The protein content is estimated by the Bradford orLowry method. The volume of the membrane suspension is adjusted with themembrane buffer (50 mM Tris-HCl containing 0.1% BSA and 0.1 mM PMSF) togive 3.0 mg/mL (or as appropriate) of protein. The membranes arealiquoted and stored at −70° C.

[0250] C. Radioligand Binding Assay:

[0251] In wells of a 96-well format microtiter plate, is added 90, 110or 130 μL (to make up a final volume of 200 μL) of assay buffercontaining 50 mM of Tris-HCl (pH 7.4), BSA (heat inactivated,protease-free), 5 mM of 0.1% MgCl₂, 1 mg % aprotinin, 1 mg % leupeptin,2 mg % 1,10-phenanthroline, 10 mg % trypsin inhibitor, and 0.1 mM PMSF.The inhibitors are added on the day of the experiment. The componentsare mixed at room temperature, and then kept in ice bath followingadjustment of the pH to 7.4. To each well is added 20 μL of unlabeledoxytocin (to give a final concentration of 0.1 to 10 nM for standardcurve and 1000 nM for non specific binding) or test compounds in 50%DMSO (e.g. for final concentrations of 0.1 to 1000 nM or as appropriate)or 50% DMSO as vehicle control. For oxytocin and other peptide ligands,20 μL of 50% DMSO is added and the assay buffer volume is adjustedaccordingly.

[0252] To each well is added 50 μL of frozen membrane suspension thawedimmediately prior to use and diluted in assay buffer to the requiredconcentration (equivalent to 25 to 50 μg of protein/well as needed). 20μL of 8 nM [³H]oxytocin in the assay buffer, prepared just before use isadded and incubated at room temperature for 60 min. shaking the plate ona mechanical shaker for the first 15 min. The incubation is stopped byrapid filtration of the plate contents followed by washing with ice-coldbuffer (50 mM Tris-HCl, pH 7.4) using a cell harvester (Tomtek andPrinted filtermat-B filter paper). The filter paper is thoroughly dried(7-12 min. in a microwave oven) and impregnated with MeltiLex B/Hmelt-on scintillation wax sheets and the radioactivity counted in abetaplate scintillation counter.

[0253] Binding data is either reported as percent inhibition at acertain concentration or if an IC₅₀ was calculated, as a nanomolarconcentration. The results of these tests on representative compounds ofthis invention are shown in Table I. TABLE 1 Binding to membranes ofChinese Hamster Ovary (CHO) cell line stably transfected with humanvasopressin V_(1a) receptor subtype, human vasopressin V₂ receptorsubtype and human oxytocin receptor V₂ TO V_(1a) % inhibition %inhibition @ % inhibition @ @ 100 nM Example 100 nM (IC₅₀, nM)* 100 nM(IC₅₀, nM)* (IC₅₀, nM)* 1 (1.37) (1388) (610) 2 (3.09) (789.63)  (633.32)   3 (6.53)    7   13 4 (3.43) (1431) (617) 5 (35.80) (2722)(1192)  6 (25.06) (2413) (1388)  7 (30.7)   −2   16 8 (7.55) (1970)(769) 9 (26.67) (2007) (1229)  10 (5.31) (1802) (2221)  11 (3.66) (1368)(356) 12 (4.27) (1615) (763) 13 (9.16) (1205) (990) 14 (1.9) (143.89)  (205.43)   15 101   59   74 16 101   68   51 17 (1.03)  (227) (144) 1836    0   −5 19 27    1   3 20 (1.09) (3104) (226.81)   21 (1.73)  (376)(311) 22 (1.47)  (227) (1140)  23 (4.09) (1080) (451) 25 20    5   21 26(55.8) (139.6)  (11.3)  36 (7.95) (1513) (2073)  37 53    6   7 39 (3.0)(759.)  (383.1)  40 93   13   25 41 71   12   35 42 89   49   27 43 75   1   27 44 83   17   13 45 87   57   9 46 97   53   14 47 55   12   1648 79    7   11 49 81    1   21 50 83   52   16 52 36    7   3

[0254] The following examples are presented to illustrate rather thanlimit the scope of this invention.

EXAMPLE 1

[0255]10-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid bis-(2-hydroxy-ethyl)-amide

[0256] Step A. 4-Bromo-3-methylbenzoic Acid Methyl Ester

[0257] To a suspension of 4-bromo-3-methylbenzoic acid (10.0 g, 46.5mmol) in methanol (125 mL) was added concentrated sulfuric acid (1 mL).The reaction was heated at reflux overnight with a homogeneous solutionobtained after several minutes of heating. After cooling, the methanolwas removed in vacuo and the residue was dissolved in dichloromethaneand washed with saturated aqueous sodium bicarbonate. The organic phasewas dried over anhydrous sodium sulfate, filtered and concentrated invacuo to give 10.2 g of title compound as a brown solid, m.p. 41-43° C.

[0258]¹H NMR (DMSO-d₆, 400 MHz): δ 2.39 (s, 3H), 3.85 (s, 3H), 7.64-7.72(m, 2H), 7.88-7.89 (m, 1H).

[0259] MS [El, m/z]: 228 [M]⁺.

[0260] Anal. Calcd. for CgHgBrO₂: C 47.19, H 3.90. Found: C 47.22, H3.80.

[0261] Step B. 2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-carboxylicAcid Methyl Ester

[0262] A mixture of 4-bromo-3-methylbenzoic acid methyl ester of Step A(2.0 g, 8.7 mmol), 2-trifluoromethyl-phenyl boronic acid (1.65 g, 8.7mmol) and sodium carbonate (4.1 g, 38.7 mmol) in toluene:ethanol:water(50 mL:25 mL: 25 mL) was purged with nitrogen for 1 hour. After additionof the tetrakis(triphenylphosphine) palladium(0) catalyst (0.50 g, 0.43mmol, the reaction was heated at 100° C. overnight. The cooled reactionmixture was filtered through Celite and the cake washed with ethylacetate. The organic layer was washed with water, dried over anhydroussodium sulfate, filtered and concentrated in vacuo to give a brown oil.Purification by flash chromatography with a solvent gradient of 25% to50% dichloromethane in hexane provided 2.0 g of the title compound as acolorless oil.

[0263]¹H NMR (DMSO-d₆, 400 MHz): δ 2.03 (s, 3H), 3.88 (s, 3H), 7.26 (d,1H), 7.34 (d, 1H), 7.66 (t, 1H), 7.75 (t, 1H), 7.81-7.83 (m, 1H),7.86-7.88 (m, 1H), 7.90-7.91 (m, 1H). MS [(+)ESI, m/z]: 312 [M+NH₄]⁺.

[0264] Anal. Calcd. for C₁₆H₁₃F₃O₂: C 65.31, H 4.45. Found: C 64.92, H4.54.

[0265] Step C. 2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-carboxylicAcid

[0266] To a solution of2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-carboxylic acid methylester of Step B (1.9 g, 6.5 mmol) in tetrahydrofuran (30 mL) was added 1N sodium hydroxide (13 mL, 13 mmol). The reaction mixture was heated atreflux overnight, then cooled and acidified with 2 N hydrochloric acid.The aqueous layer was extracted with ethyl acetate and the combinedextracts were dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give 1.65 g of the title compound as a whitesolid, m.p. 171-174° C.

[0267] NMR (DMSO-d₆, 400 MHz): δ 2.02 (s, 3H), 7.23 (d, 1H), 7.34 (d,1H), 7.65 (t, 1H), 7.75 (t, 1H), 7.79-7.81 (m, 1H), 7.86-7.89 (m, 2H),13.00 (broad s, 1H).

[0268] MS [(−) ESI, m/z]: 279 [M−H]⁻.

[0269] Anal. Calcd. for C₁₅H₁₁F₃O₂: C 64.29, H 3.96. Found: C 64.26, H3.80.

[0270] Step D.(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]methanone

[0271] A suspension of2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-carboxylic acid of Step C(0.50 g, 1.78 mmol) in thionyl chloride (3 mL) was heated at reflux for90 minutes. After cooling, the thionyl chloride was removed in vacuo andthe residue dissolved in toluene. The solution was concentrated in vacuoto yield the crude acid chloride as a brown oil. The acid chloride wasdissolved in dichloromethane (5 mL) and slowly added to a solution of10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.49 g, 2.66 mmol)and N,N-diisopropylethyl amine (0.68 mL, 3.90 mmol) in dichloromethane(15 mL). After stirring for 2 hours, the reaction was quenched withwater. The organic layer was sequentially washed with 1 N hydrochloricacid, 1 N sodium hydroxide and brine, dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo to give a yellow foam.Purification by flash chromatography using a solvent gradient of 15 to25% ethyl acetate in hexane gave a white foam which was crystallized bysonication from ethanol/hexane to provide the title compound (0.55 g) asa white solid, m.p. 127-130° C.

[0272]¹H NMR (DMSO-d₆, 400 MHz): δ 1.86 (s, 3H), 4.80-5.40 (br, 4H),5.93-5.98 (m, 2H), 6.85 (t, 1H), 6.91-6.96 (m, 2H), 7.03-7.05 (m, 1H),7.10-7.14 (m, 1H), 7.19-7.24 (m, 2H), 7.29 (s, 1H), 7.47-7.49 (m, 1H),7.61 (t, 1H), 7.70 (t, 1H), 7.81 (d, 1H).

[0273] MS [El, m/z]: 446 [M]⁺.

[0274] Anal. Calcd. for C₂₇H₂₁F₃N₂O: C 72.64, H 4.74, N 6.27. Found: C72.48, H 4.57, N 6.16.

[0275] Step E.2,2,2-Trichloro-1-(10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)ethanone

[0276] To a solution of(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]methanoneof Step D (1.87 g, 4.19 mmol) in dichloromethane (20 mL) was addedN,N-diisopropylethylamine (1.46 mL, 8.38 mmol) followed by the slowaddition of trichloroacetyl chloride (1.45 mL, 13.0 mmol). The reactionmixture was stirred overnight at room temperature, and then quenchedwith water. The organic phase was washed with 0.1 N hydrochloric acidfollowed by water, then dried over anhydrous sodium sulfate, filteredand concentrated in vacuo to give a green oil. Purification by flashchromatography on silica gel using a solvent system of 20% ethyl acetatein hexane provided 2.2 g of title product as a pale, yellow foam.

[0277]¹H NMR (DMSO-d₆, 400 MHz): δ 1.84 (s, 3H), 5.25 (br, 2H), 5.97(br, 2H), 6.37 (d, 1H), 6.89-6.92 (m, 2H), 7.02-7.04 (m, 1H), 7.06-7.10(m, 1H), 7.15-7.22 (m, 2H), 7.28 (s, 1H), 7.41-7.46 (m, 2H), 7.58 (t,1H), 7.67 (t, 1H), 7.79 (d, 1H).

[0278] MS [(+)APCI, m/z]: 591 [M+H]⁺.

[0279] Anal. Calcd. for C₂₉H₂₀Cl₃F₃N₂O₂+0.20 C₄H₈O₂+0.80H₂O: C 57.37, H3.75, N 4.49. Found: C 57.06, H 3.39, N 4.50.

[0280] Step F.10-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicAcid

[0281] To a solution of2,2,2-trichloro-1-(10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)ethanoneof Step E (2.3 g, 3.9 mmol) in acetone (20 mL) was added 2.5 N sodiumhydroxide (3.1 mL, 7.8 mmol). After stirring overnight, the reactionmixture was acidified with 2 N hydrochloric acid (4.3 mL, 8.6 mmol) andthen concentrated in vacuo. The residue was partitioned between ethylacetate and water. The organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo to give a brown solid.Trituration with diethyl ether/hexane provided the title compound (1.32g) as a white solid, m.p. 233-235° C.

[0282]¹H NMR (DMSO-d₆, 400 MHz): δ 1.84 (s, 3H), 5.17 (br, 2H), 5.94(br, 2H), 6.10-6.11 (m, 1H), 6.76 (d, 1H), 6.85-6.91 (m, 2H), 7.00-7.06(m, 2H), 7.12-7.16 (m, 1H), 7.21 (d, 1H), 7.25 (s, 1H), 7.32-7.34 (m,1H), 7.59 (t, 1H), 7.68 (t, 1H), 7.79 (d, 1H), 12.33 (br, 1H).

[0283] MS [(+)ESI, m/z]: 491 [M+H]⁺.

[0284] Anal. Calcd. for C₂₈H₂₁F₃N₂O₃: C 68.57, H 4.32, N 5.71. Found: C68.39, H 4.25, N 5.64.

[0285] Step G.10-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicAcid bis-(2-hydroxy-ethyl)-amide

[0286] To a solution of10-[(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid of Step F (0.50 g, 1.02 mmol) and diethanolamine (0.13 g, 1.24mmol) in N,N-dimethylformamide (4 mL) was added 1-hydroxybenzotriazole(0.15 g, 1.11 mmol) and 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimidehydrochloride (0.22 g, 1.15 mmol) followed by N,N-diisopropylethyl amine(0.27 mL, 1.55 mmol). The reaction mixture was stirred overnight, thendiluted with ethyl acetate and washed with water and saturated aqueoussodium bicarbonate. The organic phase was then dried over anhydroussodium sulfate, filtered and concentrated in vacuo to give an orangeoil. Purification by flash chromatography on silica gel using a solventsystem of 5% methanol in chloroform provided the title compound (0.46 g)as a white foam.

[0287]¹H NMR (DMSO-d₆, 400 MHz): δ 1.83 (s, 3H), 3.55 (br, 8H), 4.82 (t,2H), 5.15 (br, 2H), 5.33 (s, 2H), 6.02 (d, 1H), 6.29 (d, 1H), 6.85-6.90(m, 2H), 6.99-7.06 (m, 2H), 7.13 (t, 1H), 7.21 (d, 1H), 7.25 (s, 1H),7.35-7.37 (m, 1H), 7.58 (t, 1H), 7.68 (t, 1H), 7.79 (d, 1H).

[0288] MS [(+)ESI, m/z]: 578 [M+H]⁺.

[0289] Anal. Calcd. for C₃₂H₃₀F₃N₃O₄+0.60H₂O: C 65.32, H 5.34, N 7.14.Found: C 64.92, H 5.44, N 7.07.

EXAMPLE 2

[0290]10-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid (2,3-dihydroxy-propyl)-methyl-amide

[0291] To a solution of10-[(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid of Example 1, Step F (1.2 g, 2.44 mmol) and3-methylamino-1,2-propanediol (0.32 g, 3.04 mmol) in N,N-dimethylformamide (10 mL) was added 1-hydroxybenzotriazole (0.36 g, 2.66 mmol)and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.52g, 2.71 mmol) followed by N,N-diisopropylethyl amine (0.64 mL, 3.67mmol). The reaction mixture was stirred overnight, diluted with ethylacetate and washed with water and saturated aqueous sodium bicarbonate.The organic phase was then dried over anhydrous sodium sulfate, filteredand concentrated in vacuo to give a brown foam. Purification by flashchromatography using a solvent system of 5% methanol in chloroform gavea white foam, which was crystallized from ethyl acetate to provide 1.15g of title product as a white solid, m.p. 169-172° C.

[0292]¹H NMR (DMSO-d₆, 400 MHz): δ 1.83 (s, 3H), 3.08 (br, 3H), 3.34(br, 2H), 3.51 (br, 2H), 3.78 (br, 1H), 4.61 (br, 1H), 4.89 (br, 1H),5.15 (br, 2H), 5.38 (br, 2H), 6.02-6.03 (m, 1H), 6.32 (d, 1H), 6.86-6.91(m, 2H), 6.99-7.07 (m, 2H), 7.14 (t, 1H), 7.21 (d, 1H), 7.25 (s, 1H),7.37-7.39 (m, 1H), 7.58 (t, 1H), 7.68 (t, 1H), 7.79 (d, 1H).

[0293] MS [(+)APCI, m/z]: 578 [M+H]⁺.

[0294] Anal. Calcd. for C₃₂H₃₀F₃N₃O₄: C 66.54, H 5.24, N 7.27. Found: C66.14, H 5.25, N 7.04.

EXAMPLE 3

[0295]10-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid(2-hydroxy-1,1-bis-hydroxymethyl-ethyl)-amide

[0296] To a solution of10-[(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid of Example 1, Step F (0.50 g, 1.02 mmol) and2-amino-2-hydroxymethyl-1,3-propanediol (0.15 g, 1.24 mmol) inN,N-dimethylformamide (5 mL) was added 1-hydroxybenzotriazole (0.15 g,1.11 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (0.22 g, 1.15 mmol) followed by N,N-diisopropylethyl amine(0.27 mL, 1.55 mmol). The reaction mixture was stirred overnight,diluted with ethyl acetate and washed with water and saturated aqueoussodium bicarbonate. The organic phase was then dried over anhydroussodium sulfate, filtered and concentrated in vacuo to give a brown oil.Purification by flash chromatography using a solvent system of 5%methanol in chloroform provided the title product, which was redissolvedin dichloromethane and evaporated to dryness in vacuo to a white foam(0.19 g).

[0297]¹H NMR (DMSO-d₆, 400 MHz): δ 1.84 (s, 3H), 3.67 (d, 6H), 4.76 (t,3H), 5.15 (br, 2H), 5.82 (br, 2H), 6.05 (d, 1H), 6.58 (d, 1H), 6.82-6.84(m, 1H), 6.89-6.91 (m, 2H), 6.98-7.03 (m, 2H), 7.10-7.14 (m, 1H), 7.21(d, 1H), 7.24 (s, 1H), 7.33-7.35 (m, 1H), 7.59 (t, 1H), 7.68 (t, 1H),7.80 (d, 1H).

[0298] MS [(+)APCI, m/z]: 594 [M+H]⁺.

[0299] Anal. Calcd. for C₃₂H₃₀F₃N₃O₅+0.14 CH₂Cl₂+0.25H₂O: C 63.28, H5.09, N 6.89. Found: C 62.94, H 5.22, N 6.71.

EXAMPLE 4

[0300]10-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid methyl-((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy-hexyl)-amide

[0301] To a solution of10-[(2-methyl-2′-trifluoromethyl-[1.1°-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid of Example 1, Step F (1.0 g, 2.04 mmol), and N-methyl-D-glucamine(0.48 g, 2.46 mmol) in N,N-dimethylformamide (8 mL) was added1-hydroxybenzotriazole (0.30 g, 2.22 mmol) and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.43 g,2.24 mmol) followed by N,N-diisopropylethyl amine (0.55 mL, 3.09 mmol).The reaction mixture was stirred overnight, diluted with ethyl acetateand washed with water and saturated aqueous sodium bicarbonate. Theorganic phase was then dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give a yellow foam. Purification by flashchromatography on silica gel using a solvent system of 10% methanol inchloroform provided 1.08 g of title compound as a white foam.

[0302]¹H NMR (DMSO-d₆, 400 MHz): δ 1.84 (s, 3H), 3.06 (br, 3H),3.35-3.57 (m, 7H), 3.92 (br, 1H), 4.31-4.39 (m, 3H), 4.49-4.50 (m, 1H),4.89 (d, 1H), 5.15 (br, 2H), 5.38 (s, 2H), 6.02 (br, 1H), 6.34 (br, 1H),6.85-6.91 (m, 2H), 6.99-7.06 (m, 2H), 7.14 (t, 1H), 7.21 (d, 1H), 7.25(s, 1H), 7.39-7.41 (m, 1H), 7.58 (t, 1H), 7.68 (t, 1H), 7.79 (d, 1H).

[0303] MS [(+)APCI, m/z]: 668 [M+H]⁺.

[0304] Anal. Calcd. for C₃₅H₃₆F₃N₃O₇+0.38 C₄H₈O₂: C 62.56, H 5.61, N5.99. Found: C 61.22, H 5.57, N 5.80.

EXAMPLE 5

[0305](2S)-3-{4-[(10-{[2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)carbonyl]piperazin-1-yl}propane-1,2-diol

[0306] Step A.4-[[10,11-Dihydro-10-[[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]carbonyl]-1-piperazineCarboxylic Acid, Tert-Butyl Ester

[0307]10-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid of Example 1, Step F (1.0 g, 2.04 mmol),1-(tert-butoxycarbonyl)piperazine (0.46 g, 2.47 mmol) and1-hydroxybenzotriazole monohydrate (0.30 g, 2.22 mmol) were dissolved inN,N-dimethylformamide (8 mL). 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.43 g, 2.24 mmol) was then added followedby N,N-diisopropylethyl amine (0.55 mL, 3.09 mmol). The reaction mixturewas stirred overnight, diluted with ethyl acetate and washed with waterand saturated aqueous sodium bicarbonate. The organic phase was thendried over anhydrous sodium sulfate, filtered and concentrated in vacuoto give a brown oil. Purification by flash chromatography using asolvent gradient from 30% to 50% ethyl acetate in hexane provided thedesired title compound, which was redissolved in dichloromethane andevaporated to dryness in vacuo to a white foam (1.1 g).

[0308]¹H NMR (DMSO-d₆, 400 MHz): δ 1.41 (s, 9H), 1.83 (s, 3H), 3.38 (br,4H), 3.59-3.61 (m, 4H), 5.15 (br, 2H), 5.41 (s, 2H), 6.07 (d, 1H), 6.28(d, 1H), 6.85-6.90 (m, 2H), 6.99-7.06 (m, 2H), 7.12-7.16 (m, 1H), 7.21(d, 1H), 7.25 (s, 1H), 7.40-7.42 (m, 1H), 7.58 (t, 1H), 7.67 (t, 1H),7.79 (d, 1H).

[0309] MS [(+)APCI, m/z]: 659 [M+H]⁺.

[0310] Anal. Calcd. for C₃₇H₃₇F₃N₄O₄+0.09 CH₂Cl₂+0.18 C₄H₈O₂: C 66.56, H5.71, N 8.21. Found: C 66.27, H 5.40, N 8.00.

[0311] Step B.10,11-Dihydro-10-[[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl]-3-(1-piperazinylcarbonyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepineHydrochloride Salt

[0312] The4-[[10,11-dihydro-10-[[2-methyl-2′-trifluoromethyl[1,1′-biphenyl]-4-yl]carbonyl]-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]carbonyl]-1-piperazinecarboxylic acid, tert-butyl ester of Step A (0.85 g, 1.29 mmol) wasadded in one portion to stirred ethyl acetate (10 mL) saturated withhydrogen chloride gas at 0° C. The reaction mixture was stirred for 90minutes under nitrogen. A precipitate formed after several minutes. Thereaction was then warmed to room temperature and diluted with diethylether. The precipitated product was collected by filtration and driedunder high vacuum to provide 0.65 g of the title compound hydrochloridesalt as an off-white foam.

[0313]¹H NMR (DMSO-d₆, 400 MHz): δ 1.84 (s, 3H), 3.16 (br, 4H),3.83-3.85 (m, 4H), 5.15 (br, 2H), 5.43 (s, 2H), 6.09 (d, 1H), 6.38 (d,1H), 6.87-6.91 (m, 2H), 6.99-7.01 (m, 1H), 7.06 (t, 1H), 7.13-7.17 (m,1H), 7.21 (d, 1H), 7.26 (s, 1H), 7.44-7.46 (m, 1H), 7.59 (t, 1H), 7.68(t, 1H), 7.79 (d, 1H), 9.28 (br, 2H).

[0314] MS [(+)APCI, m/z]: 559 [M+H]⁺.

[0315] Anal. Calcd. for C₃₂H₂₉F₃N₄O₂+1.0 HCl+1.00H₂O+0.06 C₄H₁₀O: C62.70, H 5.32, N 9.07. Found: C 62.42, H 5.22, N 8.94.

[0316] Step C.(2S)-3-{4-[(10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)carbonyl]piperazin-1-yl}propane-1,2-diol

[0317] To a solution of10,11-dihydro-10-[[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl]-3-(1-piperazinylcarbonyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepinehydrochloride salt of Step B (0.50 g, 0.84 mmol) andN,N-diisopropylethyl amine (0.16 mL, 0.92 mmol) in methanol (5 mL) wasadded (R )-(+)-glycidol (0.10 mL, 1.50 mmol). The reaction mixture washeated to 60° C. for 4 hours then cooled and concentrated in vacuo. Theresidue was partitioned between dichloromethane and water. The organiclayer was dried over anhydrous sodium sulfate, filtered and concentratedin vacuo to give a white foam. Purification by flash chromatography onsilica gel using a solvent system of 5% methanol in chloroform providedthe title product, which was redissolved in dichloromethane andevaporated to dryness in vacuo to a white foam (0.38 g).

[0318]¹H NMR (DMSO-d₆, 400 MHz): δ 1.83 (s, 3H), 2.24-2.29 (m, 1H),2.39-2.46 (m, 5H), 3.31-3.36 (m, 2H), 3.60-3.65 (m, 5H), 4.43 (d, 1H),4.50 (br, 1H), 5.15 (br, 2H), 5.40 (s, 2H), 6.06 (d, 1H), 6.23 (d, 1H),6.84-6.90 (m, 2H), 6.99-7.06 (m, 2H), 7.12-7.16 (m, 1H), 7.21 (d, 1H),7.25 (s, 1H), 7.37-7.40 (m, 1H), 7.58 (t, 1H), 7.68 (t, 1H), 7.79 (d,1H).

[0319] MS [(+)APCI, m/z]: 633 [M+H]⁺.

[0320] Anal. Calcd. for C₃₅H₃₅F₃N₄O₄+0.50H₂O+0.15 CH₂Cl₂: C 64.51, H5.59, N 8.56. Found: C 64.20, H 5.21, N 8.41.

EXAMPLE 6

[0321](2R)-3-{4-[(10-{[2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)carbonyl]piperazin-1-yl}propane-1,2-diol

[0322] To a solution of10,11-dihydro-10-[[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl]-3-(1-piperazinylcarbonyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepinehydrochloride salt of Example 5, Step B (0.50 g, 0.84 mmol) andN,N-diisopropylethyl amine (0.16 mL, 0.92 mmol) in methanol (5 mL) wasadded (S)-(−)-glycidol (0.10 mL, 1.51 mmol). The reaction mixture washeated to 60° C. for 4 hours then cooled and concentrated in vacuo. Theresidue was partitioned between dichloromethane and water. The organiclayer was dried over anhydrous sodium sulfate, filtered and concentratedin vacuo to give a white foam. Purification by flash chromatography onsilica gel using a solvent system of 5% methanol in chloroform providedthe title product, which was redissolved in dichloromethane andevaporated to dryness in vacuo to a white foam (0.36 g).

[0323]¹H NMR (DMSO-d₆, 400 MHz): δ 1.83 (s, 3H), 2.24-2.29 (m, 1H),2.39-2.46 (m, 5H), 3.32-3.35 (m, 2H), 3.60-3.65 (m, 5H), 4.43 (d, 1H),4.50 (br, 1H), 5.15 (br, 2H), 5.40 (s, 2H), 6.06 (d, 1H), 6.23 (d, 1H),6.85-6.90 (m, 2H), 6.99-7.06 (m, 2H), 7.12-7.16 (m, 1H), 7.21 (d, 1H),7.25 (s, 1H), 7.38-7.40 (m, 1H), 7.58 (t, 1H), 7.68 (t, 1H), 7.79 (d,1H).

[0324] MS [(+)APCI, m/z]: 633 [M+H]⁺.

[0325] Anal. Calcd. for C₃₅H₃₅F₃N₄O₄+0.20 CHCl₃+0.10 CH₂Cl₂: C 63.75, H5.37, N 8.42. Found: C 63.03, H 4.93, N 8.29.

EXAMPLE 7

[0326] Methyl2-{4-[(10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)carbonyl]piperazin-1-yl}ethylether

[0327] To a solution of10-[(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid of Example 1, Step F (0.50 g, 1.02 mmol) and1-methoxyethylpiperazine (0.18 mL, 1.25 mmol) in N,N-dimethylformamide(4 mL) was added 1-hydroxybenzotriazole (0.15 g, 1.11 mmol) and1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (0.22 g,1.15 mmol) followed by N,N-diisopropylethyl amine (0.27 mL, 1.55 mmol).The reaction mixture was stirred overnight, diluted with ethyl acetateand washed with water and saturated aqueous sodium bicarbonate. Theorganic phase was then dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give a yellow oil. Purification by flashchromatography using a solvent system of 5% methanol in chloroform gavea white foam which was crystallized from diethyl ether to provide 0.32 gof title product as a white solid, m.p. 140-144° C.

[0328]¹H NMR (DMSO-d₆, 400 MHz): δ 1.83 (s, 3H), 2.40-2.47 (m, 4H), 2.50(t, 2H), 3.22 (s, 3H), 3.44 (t, 2H), 3.58-3.63 (m, 4H), 5.15 (br, 2H),5.40 (s, 2H), 6.06 (d, 1H), 6.23 (d, 1H), 6.86-6.90 (m, 2H), 6.98-7.04(m, 2H), 7.12-7.16 (m, 1H), 7.21 (d, 1H), 7.25 (s, 1H), 7.37-7.40 (m,1H), 7.58 (t, 1H), 7.68 (t, 1H), 7.79 (d, 1H).

[0329] MS [(+)APCI, m/z]: 617 [M+H]⁺.

[0330] Anal. Calcd. for C₃₅H₃₅F₃N₄O₃: C 68.17, H 5.72, N 9.09. Found: C68.09, H 5.73, N 8.93.

EXAMPLE 8

[0331](2R)-1-Methoxy-3-{4-[(10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)carbonyl]piperazin-1-yl}propan-2-ol

[0332] To a solution of10,11-dihydro-10-[[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl]-3-(1-piperazinylcarbonyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepinehydrochloride salt of Example 5, Step B (0.50 g, 0.84 mmol) andN,N-diisopropylethyl amine (0.16 mL, 0.92 mmol) in methanol (5 mL) wasadded (R)-(−)-glycidyl methyl ether (0.11 mL, 1.22 mmol). The reactionmixture was heated to 60° C. overnight then cooled and concentrated invacuo. The residue was partitioned between dichloromethane and water.The organic layer was dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give a white foam. Purification by flashchromatography on silica gel using a solvent system of 3% methanol inchloroform provided 0.40 g of title product as a white foam.

[0333]¹H NMR (DMSO-d₆, 400 MHz): δ 1.83 (s, 3H), 2.25-2.38 (m, 2H), 2.45(br, 4H), 3.21-3.25 (m, 4H), 3.27-3.29 (m, 1H), 3.61 (br, 4H), 3.73-3.77(m, 1H), 4.57 (d, 1H), 5.15 (br, 2H), 5.40 (s, 2H), 6.05 (d, 1H), 6.22(d, 1H), 6.84-6.90 (m, 2H), 6.99-7.06 (m, 2H), 7.12-7.16 (m, 1H), 7.21(d, 1H), 7.25 (s, 1H), 7.37-7.39 (m, 1H), 7.58 (t, 1H), 7.68 (t, 1H),7.79 (d, 1H).

[0334] MS [(+)APCI, m/z]: 647 [M+H]⁺.

[0335] Anal. Calcd. for C₃₆H₃₇F₃N₄O₄+0.50H₂O: C 65.94, H 5.84, N 8.54.Found: C 65.69, H 5.50, N 8.34.

EXAMPLE 9

[0336][3-({4-[(2S)-2-Hydroxy-3-methoxypropyl]-1-piperazinyl}carbonyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl][2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]methanone

[0337] To a solution of10,11-dihydro-10-[(2-methyl-2-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-3-(1-piperazinylcarbonyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepinehydrochloride salt of Example 5, Step B (0.50 g, 0.84 mmol) andN,N-diisopropylethyl amine (0.16 mL, 0.92 mmol) in methanol (5 mL) wasadded (S)-(+)-glycidyl methyl ether (0.11 mL, 1.22 mmol). The reactionmixture was heated to 60° C. overnight then cooled and concentrated invacuo. The residue was partitioned between dichloromethane and water.The organic layer was dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give a white foam. Purification by flashchromatography using a solvent system of 3% methanol in chloroformprovided 0.40 g of title product as a white foam.

[0338]¹H NMR (DMSO-d₆, 400 MHz): δ 1.83 (s, 3H), 2.28-2.35 (m, 2H), 2.45(br, 4H), 3.21-3.25 (m, 4H), 3.28-3.30 (m, 1H), 3.61 (br, 4H), 3.74-3.76(m, 1H), 4.59 (d, 1H), 5.15 (br, 2H), 5.40 (s, 2H), 6.06 (d, 1H), 6.23(d, 1H), 6.84-6.90 (m, 2H), 6.98-7.06 (m, 2H), 7.12-7.16 (m, 1H), 7.21(d, 1H), 7.25 (s, 1H), 7.37-7.39 (m, 1H), 7.58 (t, 1H), 7.68 (t, 1H),7.79 (d, 1H).

[0339] MS [(+)APCI, m/z]: 647 [M+H]⁺.

[0340] Anal. Calcd. for C₃₆H₃₇F₃N₄O₄+1.00H₂O+0.14 CHCl₃: C 63.70, H5.78, N 8.22. Found: 63.66, H 5.38, N 8.10.

EXAMPLE 10

[0341]N-(2,3-Dimethoxypropyl)—N-methyl-10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0342] To a solution of10-[(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid (2,3-dihydroxypropyl)-methyl-amide of Example 2 (0.50 g, 0.87 mmol)in tetrahydrofuran (10 mL) was added sodium hydride (60% suspension inoil, 0.14 g, 3.5 mmol). After the gas evolution ceased, iodomethane(0.43 mL, 6.9 mmol) was added and the reaction mixture stirredovernight. Additional amounts of sodium hydride (60% suspension in oil,0.14 g, 3.5 mmol) and iodomethane (0.43 mL, 6.9 mmol) were added. After1 hour, the reaction was quenched with water and extracted withdichloromethane. The combined organic layers were dried over anhydroussodium sulfate, filtered and concentrated in vacuo to give a yellow oil.Purification by flash chromatography using a solvent system of 75% ethylacetate in hexane provided 0.46 g of title product as an off-white foam.

[0343]¹H NMR (DMSO-d₆, 400 MHz): δ 1.83 (s, 3H), 3.08 (s, 3H), 3.24 (s,3H), 3.31 (br, 2H), 3.33 (br, 3H), 3.51-3.66 (br, 3H), 5.15 (br, 2H),5.36-5.44 (m, 2H), 6.04 (d, 1H), 6.31 (d, 1H), 6.86-6.91 (m, 2H),6.99-7.07 (m, 2H), 7.13-7.17 (m, 1H), 7.21 (d, 1H), 7.25 (s, 1H),7.35-7.37 (m, 1H), 7.58 (t, 1H), 7.68 (t, 1H), 7.79 (d, 1H).

[0344] MS [ESI, m/z]: 606 [M+H]⁺.

[0345] Anal. Calcd. for C₃₄H₃₄F₃N₃O₄+0.20H₂O+0.10 C₄H₈O₂: C 66.85, H5.74, N 6.80. Found: C 66.59, H 5.52, N 6.74.

EXAMPLE 11

[0346]10-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic Acidmethyl-[(2-oxo-[1,3]dioxolan-4-yl)methyl]-amide

[0347] To a solution of10-[(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid (2,3-dihydroxypropyl)-methyl-amide of Example 2 (0.50 g, 0.87 mmol)in dichloromethane (17 mL) at 0° C. was added N,N-diisopropylethyl amine(0.30 mL, 1.72 mmol) followed by 1,1′-carbonyldiimidazole (0.14 g, 0.87mmol). The reaction was allowed to warm to room temperature whilestirring overnight then concentrated in vacuo to give a white solid. Theresidue was partitioned between dichloromethane and water. The organiclayer was dried over anhydrous sodium sulfate, filtered and concentratedin vacuo to give a white foam. Purification by flash chromatographyusing a solvent system of 80% ethyl acetate in hexane provided the titleproduct, which was redissolved in dichloromethane and evaporated todryness in vacuo to a white foam (0.48 g).

[0348]¹H NMR (DMSO-d₆, 400 MHz): 61.83 (s, 3H), 3.08 (s, 3H), 3.27-3.30(m, 1H), 3.74-3.79 (m, 1H), 3.91-3.96 (m, 1H), 4.26-4.30 (m, 1H), 4.62(t, 1H), 5.08-5.15 (m, 2H), 5.37-5.45 (m, 2H), 6.07 (d, 1H), 6.35 (d,1H), 6.86-6.91 (m, 2H), 7.00-7.07 (m, 2H), 7.14 (t, 1H), 7.21 (d, 1H),7.25 (s, 1H), 7.38-7.40 (m, 1H), 7.58 (t, 1H), 7.68 (t, 1H), 7.79 (d,1H).

[0349] MS [(+)ESI, m/z]: 604 [M+H]⁺.

[0350] Anal. Calcd. for C₃₃H₂₈F₃N₃O₅+0.08 CH₂Cl₂+0.07 C₄H₈O₂: C 64.99, H4.70, N 6.82. Found: C 64.38, H 4.62, N 6.71.

EXAMPLE 12

[0351]N-[((4S,5S)-5-{(R)-Hydroxy[(4R)-2-oxo-1,3-dioxolan-4-yl]methyl}-2-oxo-1,3-dioxolan-4-yl)methyl]-N-methyl-10-{[2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c]benzodiazepine-3-carboxamide

[0352] To a solution of10-[(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid methyl-((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy-hexyl)-amide ofExample 4 (0.35 g, 0.52 mmol) in dichloromethane (10 mL) at 0° C. wasadded N,N-diisopropylethyl amine (0.37 mL, 2.12 mmol) followed by1,1′-carbonyldiimidazole (0.17 g, 1.05 mmol). The reaction mixture wasallowed to warm to room temperature while stirring and after 4 hours wasconcentrated in vacuo to give a white solid. The residue was partitionedbetween dichloromethane and water. The organic layer was dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to give awhite foam. Purification by flash chromatography on silica gel using asolvent system of 75% ethyl acetate in hexane provided title product,which was redissolved in dichloromethane and evaporated to dryness invacuo to yield a white foam (0.26 g).

[0353]¹H NMR (DMSO-d₆, 400 MHz): δ 1.83 (s, 3H), 3.16 (s, 3H), 3.79-3.84(m, 1H), 3.98-4.05 (m, 2H), 4.39-4.43 (m, 1H), 4.57 (t, 1H), 4.75 (br,1H), 4.85-4.90 (m, 1H), 4.92-4.96 (m, 1H), 5.15 (br, 2H), 5.42 (q, 2H),6.08 (d, 1H), 6.35 (d, 1H), 6.39 (d, 1H), 6.86-6.91 (m, 2H), 7.00-7.07(m, 2H), 7.13-7.17 (m, 1H), 7.21 (d, 1H), 7.25 (s, 1H), 7.38-7.40 (m,1H), 7.58 (t, 1H), 7.68 (t, 1H), 7.79 (d, 1H).

[0354] MS [(+)ESI, m/z]: 720 [M+H]⁺.

[0355] Anal. Calcd. for C₃₇H₃₂F₃N₃O₉+0.28 C₄H₈O₂+0.08 CH₂Cl₂: C 61.08, H4.62, N 5.59. Found: C 60.63, H 4.56, N 5.40.

EXAMPLE 13

[0356]2-(Acetyloxy)-1-({methyl[(10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)carbonyl]amino}methyl)ethylAcetate

[0357] To a solution of10-[(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid (2,3-dihydroxypropyl)-methyl-amide of Example 2 (0.53 g, 0.90 mmol)in dichloromethane (2 mL) was added triethylamine (0.40 mL, 2.87 mmol)and a catalytic amount of 4-(dimethylamino) pyridine (10 mg, 0.082mmol). After addition of acetic anhydride (0.37 mL, 3.92 mmol), thereaction mixture was stirred for 1 hour and then concentrated in vacuo.The residue was partitioned between water and diethyl ether. The organiclayer was washed with 5% aqueous sodium bicarbonate, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to provide0.52 g of title product as a white foam.

[0358]¹H NMR (DMSO-d₆, 400 MHz): δ 1.83 (s, 3H), 1.99 (s, 3H), 2.03 (s,3H), 3.09 (br, 3H), 3.65-3.75 (br m, 2H), 4.08-4.12 (m, 1H), 4.22-4.26(m, 1H), 5.15 (br, 2H), 5.36-5.41 (m, 3H), 6.06 (d, 1H), 6.31 (d, 1H),6.86-6.91 (m, 2H), 6.99-7.07 (m, 2H), 7.13-7.17 (m, 1H), 7.21 (d, 1H),7.25 (s, 1H), 7.39-7.41 (m, 1H), 7.58 (t, 1H), 7.68 (t, 1H), 7.79 (d,1H).

[0359] MS [(+)APCI, m/z]: 662 [M+H]⁺.

[0360] Anal. Calcd. for C₃₆H₃₄F₃N₃O₆: C 65.35, H 5.18, N 6.35. Found: C64.81, H 5.05, N 6.26.

EXAMPLE 14

[0361]10-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid (2,3-dihydroxy-propyl)-methyl-amide

[0362] Step A. 2-Methyl-2′-methoxy-[1,1′-biphenyl]-4-carboxylic AcidMethyl Ester

[0363] A mixture of 3-methyl-4-bromobenzoic acid methyl ester (2.0 g,8.7 mmol), 2-methoxyphenyl boronic acid (1.32 g, 8.7 mmol) and sodiumcarbonate (4.1 g, 38.7 mmol) in toluene:ethanol:water (50 mL:25 mL: 25mL), was purged with nitrogen for 1 hour. After addition of thetetrakis(triphenylphosphine) palladium(0) catalyst (0.50 g, 0.43 mmol),the reaction mixture was heated at 100° C. overnight. After cooling, thereaction was filtered through Celite and the cake washed with ethylacetate. The organic layer was washed with water, dried over anhydroussodium sulfate, filtered and concentrated in vacuo to give a brown oil.Purification by flash chromatography with a solvent gradient from 20% to50% dichloromethane in hexane gave 2.0 g of product as a colorless oil.

[0364]¹H NMR (DMSO-d₆, 400 MHz): δ 2.09 (s, 3H), 3.70 (s, 3H), 3.85 (s,3H), 7.00-7.04 (m, 1H), 7.08-7.11 (m, 2H), 7.23 (d, 1H), 7.37-7.41 (m,1H), 7.77-7.79 (m, 1H), 7.83-7.84 (m, 1H).

[0365] MS [(+)APCI, m/z]: 257 [M+H]⁺.

[0366] Anal. Calcd. for C₁₆H₁₆0₃: C 74.98, H 6.29. Found: C 74.06, H6.17.

[0367] Step B. 2-Methyl-2′-methoxy-[1,1′-biphenyl]-4-carboxylic Acid

[0368] The 2-methyl-2′-methoxy-[1,1′-biphenyl]-4-carboxylic acid methylester of Step A (1.9 g, 7.4 mmol) was dissolved in tetrahydrofuran (30mL) and 1 N sodium hydroxide (15 mL, 15 mmol) was added. The reactionmixture was heated at reflux overnight, then cooled and acidified with 2N hydrochloric acid. The aqueous layer was extracted with ethyl acetate.The combined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated in vacuo to give 1.6 g of product as a whitesolid, m.p. 160-162° C.

[0369]¹H NMR (DMSO-d₆, 400 MHz): δ 2.09 (s, 3H), 3.70 (s, 3H), 7.00-7.03(m, 1H), 7.08-7.10 (m, 2H), 7.20 (d, 1H), 7.36-7.40 (m, 1H), 7.75-7.78(m, 1H), 7.82 (s, 1H), 12.85 (br, 1H).

[0370] MS [(−) APCI, m/z]: 241 [M−H]⁻.

[0371] Anal. Calcd. for C₁₅H₁₄O₃: C 74.36, H 5.82. Found: C 73.93, H5.71.

[0372] Step C.(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)-methanone

[0373] The 2-methyl-2′-methoxy-[1,1′-biphenyl]-4-carboxylic acid of StepB (0.50 g, 2.06 mmol) was suspended in thionyl chloride (3 mL) and themixture heated at reflux for 30 minutes. After cooling, the thionylchloride was removed in vacuo. The residue was dissolved in toluene andconcentrated in vacuo to give the crude acid chloride as a brown oil.The acid chloride was then dissolved in dichloromethane (5 mL) andslowly added to a solution of10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.57 g, 3.10 mmol)and N,N-diisopropylethyl amine (0.79 mL, 4.53 mmol) in dichloromethane(15 mL). After stirring for 1 hour, the reaction was quenched withwater. The organic layer was washed with 1 N hydrochloric acid, 1 Nsodium hydroxide and brine, dried over anhydrous sodium sulfate,filtered and concentrated in vacuo to give a yellow foam. Purificationby flash chromatography on silica gel using a solvent gradient of 15 to25% ethyl acetate in hexane yielded a white foam which crystallized uponsonication with ethanol/hexane to give 0.42 g of the desired titleproduct as a white solid, m.p. 133-135 oc.

[0374]¹H NMR (DMSO-d₆, 400 MHz): δ 1.93 (s, 3H), 3.65 (s, 3H), 4.80-5.40(br, 4H), 5.92-5.96 (m, 2H), 6.81-6.82 (m, 1H), 6.89-6.91 (m, 1H),6.95-7.05 (m, 5H), 7.16-7.25 (m, 3H), 7.31-7.35 (m, 1H), 7.47-7.49 (m,1H).

[0375] MS [(+)ESI, m/z]: 409 [M+H]⁺.

[0376] Anal. Calcd. for C₂₇H₂₄N₂O₂: C 79.39, H 5.92, N 6.86. Found: C79.16, H 5.87, N 6.90.

[0377] Step D.2,2,2-Trichloro-1-{10-[(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone

[0378] To a solution of(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)-methanoneof Step C (1.5 g, 3.67 mmol) in dichloromethane (20 mL) was addedN,N-diisopropylethyl amine (1.28 mL, 7.35 mmol) followed by slowaddition of trichloroacetyl chloride (1.23 mL, 11.0 mmol). The reactionmixture was stirred overnight at room temperature then quenched withwater. The organic phase was washed with 0.1 N hydrochloric acidfollowed by water, then dried over anhydrous sodium sulfate, filteredand concentrated in vacuo to give a green oil. Purification by flashchromatography on silica gel using a solvent system of 20% ethyl acetatein hexane provided the title compound, which was redissolved indichloromethane and evaporated to dryness in vacuo to a yellow foam (2.1g).

[0379]¹H NMR (DMSO-d₆, 400 MHz): δ 1.94 (s, 3H), 3.65 (s, 3H), 5.25 (br,2H), 5.97 (br, 2H), 6.36-6.37 (m, 1H), 6.90-6.92 (m, 1H), 6.96-7.06 (m,5H), 7.15-7.23 (m, 2H), 7.26 (s, 1H), 7.32-7.36 (m, 1H), 7.44-7.47 (m,2H).

[0380] MS [(+)APCI, m/z]: 553 [M+H]⁺.

[0381] Anal. Calcd. for C₂₉H₂₃C₁₃N₂O₃+0.13 C₄H₈O₂+0.13 CH₂Cl₂:C 61.79, H4.25, N 4.86. Found: C 60.43, H 4.50, N 4.80.

[0382] Step E.10-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid

[0383] To a solution of2,2,2-trichloro-1-{10-[(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Step D (2.0 g, 3.6 mmol) in acetone (20 mL) was added 2.5 Nsodium hydroxide (2.9 mL, 7.25 mmol). After stirring overnight, thereaction mixture was acidified with 2 N hydrochloric acid (4.0 mL, 8.0mmol) then concentrated in vacuo. The residue was partitioned betweenethyl acetate and water. The organic layer was dried over anhydroussodium sulfate, filtered and concentrated in vacuo to give a brownsolid. Trituration with diethyl ether-hexane provided 1.4 g of thedesired product as a white solid, m.p. 174-184° C.

[0384]¹H NMR (DMSO-d₆, 400 MHz): δ 1.93 (s, 3H), 3.65 (s, 3H), 5.17 (br,2H), 5.94 (br, 2H), 6.09-6.10 (m, 1H), 6.77 (d, 1H), 6.89-7.06 (m, 6H),7.10-7.19 (m, 2H), 7.23 (s, 1H), 7.31-7.38 (m, 2H), 12.31 (br, 1H).

[0385] MS [(−)APCI, m/z]: 451 [M−H]⁻.

[0386] Anal. Calcd. for C₂₈H₂₄N₂O₄+0.10 C₄H₁₀O: C 74.17, H 5.48, N 6.09.Found: C 73.63, H 5.68, N 5.94.

[0387] Step F.10-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicAcid (2,3-dihydroxy-propyl)-methyl-amide

[0388] To a solution of10-[(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H—pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step E (0.50 g,1.10 mmol) and 3-methylamino-1,2-propanediol (0.14 mL, 1.33 mmol) inN,N-dimethylformamide (4 mL) was added 1-hydroxybenzotriazolemonohydrate (0.16 g, 1.18 mmol) and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.23 g,1.20 mmol) followed by N,N-diisopropylethyl amine (0.29 mL, 1.66 mmol).The reaction mixture was stirred overnight, diluted with ethyl acetateand washed with water and saturated aqueous sodium bicarbonate. Theorganic phase was then dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give a yellow oil. Purification by flashchromatography using a solvent system of 3% methanol in chloroform gavea white foam which was crystallized by trituration with diethylether-hexane to provide 0.11 g of title product as a white amorphoussolid.

[0389]¹H NMR (DMSO-d₆, 400 MHz): δ 1.93 (s, 3H), 3.08 (br, 3H), 3.34(br, 1H), 3.51 (br, 2H), 3.65 (s, 3H), 3.78 (br, 1H), 4.62 (t, 1H), 4.91(br, 1H), 5.15 (br, 2H), 5.35-5.42 (br m, 2H), 6.02-6.03 (m, 1H), 6.33(d, 1H), 6.89 (d, 1H), 6.94-7.00 (m, 4H), 7.04 (d, 1H), 7.11-7.20 (m,3H), 7.23 (s, 1H), 7.31-7.35 (m, 1H), 7.40-7.42 (m, 1H).

[0390] MS [(+)APCI, m/z]: 540 [M+H]⁺.

[0391] Anal. Calcd. for C₃₂H₃₃N₃O₅+0.40H₂O+0.09 C₄H₁₀O: C 70.22, H 6.32,N 7.59. Found: C 70.04, H 6.26, N 7.41.

EXAMPLE 15

[0392]N-[(2S)-2,3-Dihydroxypropyl]-10-[(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0393] The title compound was obtained from the10-[(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid (2,3-dihydroxy-propyl)-methyl-amide of Example 14 by chiralseparation on a preparative Chiralpak OD HPLC column (4.6×250 mm) usinga solvent system of 50% hexane in ethanol. The homogeneous material wasredissolved in dichloromethane and evaporated to dryness in vacuo toyield a white foam (0.035 g, stereochemistry arbitrarily assigned).

[0394]¹H NMR (DMSO-d₆, 400 MHz): δ 1.93 (s, 3H), 3.08 (br, 3H), 3.34(br, 1H), 3.51 (br, 2H), 3.65 (s, 3H), 3.78 (br, 1H), 4.60 (t, 1H),4.89-4.90 (m, 1H), 5.15 (br, 2H), 5.35-5.42 (br m, 2H), 6.01-6.02 (m,1H), 6.33 (d, 1H), 6.89 (d, 1H), 6.94-7.01 (m, 4H), 7.04 (d, 1H),7.11-7.20 (m, 3H), 7.23 (s, 1H), 7.31-7.35 (m, 1H), 7.40-7.42 (m, 1H).

[0395] MS [ESI, m/z]: 540 [M+H]⁺.

[0396] Anal. Calcd. for C₃₂H₃₃N₃O₅+0.50H₂O+0.17 CH₂Cl₂: C 68.62, H 6.15,N 7.46. Found: C 68.51, H 6.28, N 7.37.

EXAMPLE 16

[0397]N-[(2R)-2,3-Dihydroxypropyl]-10-[(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0398] The title compound was obtained from the10-[(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid (2,3-dihydroxy-propyl)-methyl-amide of Example 14 by chiralseparation on a preparative Chiralpak OD HPLC column (4.6×250 mm) usinga solvent system of 50% hexane in ethanol. The homogeneous material wasredissolved in dichloromethane and evaporated to dryness in vacuo toprovide a white foam (0.020 g, stereochemistry arbitrarily assigned).

[0399]¹H NMR (DMSO-d₆, 400 MHz): δ 1.93 (s, 3H), 3.08 (br, 3H), 3.34(br, 1H), 3.51 (br, 2H), 3.65 (s, 3H), 3.78 (br, 1H), 4.60 (br, 1H),4.90 (br, 1H), 5.15 (br, 2H), 5.35-5.42 (br m, 2H), 6.02 (br, 1H), 6.33(d, 1H), 6.90 (d, 1H), 6.94-7.00 (m, 4H), 7.05 (d, 1H), 7.11-7.20 (m,3H), 7.23 (s, 1H), 7.31-7.35 (m, 1H), 7.40-7.42 (m, 1H).

[0400] MS [(+)APCI, m/z]: 540 [M+H]⁺.

[0401] Anal. Calcd. for C₃₂H₃₃N₃O₅+0.18 CH₂Cl₂: C 69.65, H 6.06, N 7.57.Found: C 69.51, H 6.07, N 7.27.

EXAMPLE 17

[0402]10-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid methyl-[(2S,3R,4R, 5R)-2,3,4,5,6-pentahydroxy-hexyl)-amide

[0403] To a solution of10-[(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid of Example 14, Step E (0.70 g, 1.55 mmol), N-methyl-D-glucamine(0.36 g, 1.84 mmol) and 1-hydroxybenzotriazole monohydrate (0.23 g, 1.72mmol) in N,N-dimethylformamide (6 mL) wad added1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (0.33 g,1.72 mmol) followed by N,N-diisopropylethyl amine (0.41 mL, 2.30 mmol).The reaction mixture was stirred overnight, then was diluted with ethylacetate and washed with water and saturated aqueous sodium bicarbonate.The organic phase was then dried over anhydrous sodium sulfate, filteredand concentrated in vacuo to give a yellow foam. Purification by flashchromatography on silica gel using a solvent system of 10% methanol inchloroform provided the title compound, which was redissolved indichloromethane and evaporated to dryness in vacuo to a pale, yellowfoam (0.63 g).

[0404]¹H NMR (DMSO-d₆, 400 MHz): 61.93 (s, 3H), 3.06 (br, 3H), 3.33-3.57(m, 7H), 3.65 (s, 3H), 3.92 (br, 1H), 4.32-4.41 (m, 3H), 4.50-4.51 (m,1H), 4.91 (d, 1H), 5.15 (br, 2H), 5.35-5.41 (m, 2H), 6.01 (br, 1H), 6.35(br, 1H), 6.90 (d, 1H), 6.94-7.00 (m, 4H), 7.04 (d, 1H), 7.11-7.20 (m,2H), 7.23 (s, 1H), 7.31-7.35 (m, 1H), 7.42-7.44 (m, 1H).

[0405] MS [(+)APCI, m/z]: 630 [M+H]⁺.

[0406] Anal. Calcd. for C₃₅H₃₉N₃O₈+0.42H₂O+0.11 CHCl₃+0.22 CH₂Cl₂: C63.42, H 6.08, N 6.28. Found: C 61.35, H 5.64, N 5.95.

EXAMPLE 18

[0407]N-(2,3-Dihydroxypropyl)-7,8-dimethoxy-N-methyl-10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0408] Step A.1-[(4,5-Dimethoxy-2-nitrophenyl)methyl]-1H-pyrrole-2-carboxaldehyde

[0409] To a suspension of sodium hydride (0.724 g, 60% suspension inoil) in N,N-dimethylformamide (50 mL) was added pyrrole 2-carboxaldehyde(1.7 g, 18.1 mmol) and the reaction mixture was stirred for 30 minutes.It was then cooled to 0° C. and 4,5-dimethoxy-2-nitrobenzyl bromide (5.0g, 1 equiv) was added dropwise over 20 minutes. After the addition, thereaction mixture was stirred at room temperature for 3 hours. It wasthen diluted with ethyl acetate (450 mL), washed with water, dried overanhydrous magnesium sulfate, filtered and evaporated to dryness. Thecrude product was triturated with water, filtered and washed with water.This material was dried over anhydrous potassium carbonate in vacuo toprovide the title compound as a yellow crystalline solid (4.97 g), m.p.109-112° C., which was used as such in the next step.

[0410] Step B.7,8-Dimethoxy-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine

[0411] A mixture of the1-[(4,5-dimethoxy-2-nitrophenyl)methyl]-1H-pyrrole-2-carboxaldehyde ofStep A (4.97 g), acetic acid (0.5 mL), magnesium sulfate (0.5 g) and 10%palladium on charcoal (0.5 g) in ethyl acetate (50 mL) was hydrogenatedovernight at atmospheric pressure. The reaction was then filteredthrough Celite and the solvent removed in vacuo to give the crude titlecompound as an amber foam (3.2 g) which was used in the next stepwithout further purification.

[0412] Step C.7,8-Dimethoxy-(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(4-bromo-3-methyl-phenyl)-methanone

[0413] To a solution of7,8-dimethoxy-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of StepB (3.20 g) in dichloromethane (20 mL) was added 3-methyl-4-bromo benzoylchloride (3.4 g, 1.1 equiv) and triethylamine (2.0 g, 1.5 equiv) and themixture was stirred at room temperature overnight. The solvent was thenremoved in vacuo and the residue chromatographed on silica gel elutingwith a solvent gradient from 5 to 50% ethyl acetate in petroleum etherto provide the title compounds as a yellow crystalline solid (3.5 g),m.p. 165-168° C.

[0414]¹H NMR (CDCl₃, 200 MHz): δ 2.30 (s, 3H), 3.55 (br, 3H), 3.85 (s,3H), 5.1 (br, 4H), 6.05 (br, 1H), 6.1 (t, 1H), 6.3 (br, 1H), 6.65 (t,1H), 6.8 (s, 2H), 7.3 (s, 2H).

[0415] MS [(+)ESI, m/z]: 442 [M+H]⁺.

[0416] Step D.7,8-Dimethoxy-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl][2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]methanone

[0417] The7,8-dimethoxy-(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(4-bromo-3-methyl-phenyl)-methanone of Step C (1.0 g) was reacted with2-trifluoromethylphenyl boronic acid (0.645 g, 1.5 equiv.), potassiumphosphate (0.964 g, 2.0 equiv.) and a catalytic amount (0.050 g) oftetrakis(triphenylphosphine) palladium(0) in refluxing dioxane (10 mL)under nitrogen for 24 hours. The reaction was then cooled to roomtemperature and the solvent removed in vacuo. The residue was dissolvedin dichloromethane and the solution was washed with water, dried overanhydrous magnesium sulfate, filtered and evaporated to dryness. Thecrude product so obtained was purified by chromatography on silica geleluting with 5% ethyl acetate in dichloromethane to provide the titleproduct as a white crystalline solid (1.0 g), m.p. 187-188° C.

[0418]¹H NMR (DMSO-d₆, 400 MHz): δ 1.85 (s, 3H), 3.40 (s, 3H), 3.70 (s,3H), 5.20 (br, 4H), 5.92 (t, 1H), 5.96 (s, 1H), 6.56 (s, 1H), 6.77 (t,1H), 6.90 (m, 1H), 7.05 (m, 2H), 7.20 (d, 1H), 7.30 (s, 1H), 7.58 (t,1H), 7.68 (t, 1H), 7.80 (d, 1H).

[0419] MS [(+)APCI, m/z]: 507 [M+H]⁺.

[0420] Anal. Calcd. for C₂₉H₂₅F₃N₂O₃: C 68.77, H 4.97, N 5.53. Found: C68.85, H 5.05, N 5.43.

[0421] Step E.N-(2,3-Dihydroxypropyl)-7,8-dimethoxy-N-methyl-10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0422] A solution of7,8-dimethoxy-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl][2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]methanone ofStep D (0.2 g, 0.39 mmol), diphosgene (1 equiv.) and triethylamine (1.5equiv.) in dichloromethane (5 mL) was stirred at room temperatureovernight. The solvent was removed in vacuo and the residue wasdissolved in dichloromethane (5 mL). To the solution was addedtriethylamine (1.5 equiv.) and 3-methylamino-1,2-propanediol (1.5equiv.) and the mixture was stirred at room temperature for 48 hours.The reaction mixture was then washed with water, dried over anhydrousmagnesium sulfate, filtered and evaporated to dryness. The residue wasfirst chromatographed on silica gel eluting with 2% methanol indichloromethane and then chromatographed again with 2% methanol in ethylacetate to provide the title compound (0.25 g) as a white solid, m.p.184-186° C.

[0423]¹H NMR (DMSO-d₆, 400 MHz): δ 1.85 (s, 3H), 3.05 (s, 3H), 3.40 (s,3H), 3.50 (br, 3H), 3.70 (s, 3H), 3.80 (br, 2H), 4.60 (t, 1H), 4.90 (s,1H), 5.25 (dd, 4H), 6.00 (s, 1H), 6.30 (d, 1H), 6.50 (s, 1H), 6.90 (s,2H), 7.05 (s, 1H), 7.20 (d, 1H), 7.30 (s, 1H), 7.60 (t, 1H), 7.70 (t,1H), 7.80 (d, 1H).

[0424] MS [(+)APCI, m/z]: 638 [M+H]⁺.

[0425] Anal. Calcd. for C₃₄H₃₄F₃N₃O₆ +H₂O: C 62.28, H 5.53, N 6.41.Found: C 62.43, H 5.64, N 6.39.

EXAMPLE 19

[0426]N,N-Bis(2-Hydroxyethyl)-7,8-dimethoxy-10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0427] A solution ofN-(2,3-dihydroxypropyl)-7,8-dimethoxy-N-methyl-10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamideof Example 18, Step D (0.31 mmol), diphosgene (1.1 equiv.) andtriethylamine (1.5 equiv.) in dichloromethane (5 mL), was stirred atroom temperature overnight. The solvent was removed in vacuo and theresidue was dissolved in dichloromethane (5 mL). To the solution wasadded triethylamine (1.5 equiv.) and diethanolamine (1.5 equiv.) and thereaction was stirred overnight. The reaction mixture was then washedwith water, dried over anhydrous magnesium sulfate, filtered andevaporated to dryness. The residue was first chromatographed on silicagel eluting with 2% methanol in dichloromethane and thenrechromatographed with 2% methanol in ethyl acetate to provide the titlecompound (0.036 g) as a white solid, m.p. 130-132° C.

[0428]¹H NMR (DMSO-d₆, 400 MHz): δ 1.85 (s, 3H), 3.40 (s, 3H), 3.60 (s,8H), 3.70 (s, 3H), 4.80 (s, 2H), 5.00 (br, 2H), 5.20 (s, 2H), 6.00 (s,1H), 6.25 (d, 1H), 6.45 (s, 1H), 6.90 (s, 1H), 6.95 (s, 1H), 7.05 (s,1H), 7.20 (d, 1H), 7.30 (s, 1H), 7.60 (t, 1H), 7.70 (t, 1H), 7.80 (d,1H).

[0429] MS [(+)APCI, m/z]: 638 [M+H]⁺.

[0430] Anal. Calcd. for C₃₄H₃₄F₃N₃O₆+H₂O: C 62.28, H 5.53, N 6.41.Found: C 62.87, H 5.40, N 6.47.

EXAMPLE 20

[0431]10-{[6-Chloro-3-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-methyl-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0432] Step A. 4-Iodo-5-chloro-2-methoxy Benzoic Acid

[0433] A stirred solution of 4-amino-5-chloro-2-methoxy benzoic acid(12.25 g , 60.8 mmol) in water (136 mL ) and concentrated sulfuric acid(34 mL) was cooled to 0° C. in a flask fitted with an overhead stirrer.A solution of sodium nitrite (4.62 g , 66.9 mmol) in water (26 mL) wasadded dropwise while keeping the internal temperature around 0° C.Potassium iodide (11.11 g, 66.9 mmol) and iodine (4.24 g, 33.5 mmol)were dissolved in water (130 mL) and added dropwise to the stirredreaction mixture. After 2 hours the reaction was extracted with ethylacetate. The organic extracts were then washed with 10% sodiumthiosulfate and brine, then dried over magnesium sulfate, filtered andevaporated to dryness to yield 11.32 g of the title compound, m.p.150°-151° C. This material was used without further purification.

[0434]¹H NMR (DMSO-d₆, 400 MHz): δ 13.03 (br, 1H), 7.70 (s, 1H), 7.63(s, 1H), 3.82 (s, 3H).

[0435] MS [(−)-APCI, m/z]: 311 [M−H]⁻.

[0436] Anal. Calcd. for C₈H₆CllO₃: C 30.75, H 1.94. Found: C 31.28, H1.78.

[0437] Step B.2-Chloro-2′-trifluoromethyl-5-methoxy-[1,1′-biphenyl]-4-carboxylic Acid.

[0438] To a stirred solution of 4-iodo-5-chloro-2-methoxy benzoic acidof Step A (3.12 g, 10 mmol) in N,N-dimethylformamide (100 mL) was added2-trifluoromethyl-phenyl boronic acid (5.70 g, 30 mmol) and potassiumcarbonate (12.73 g, 92 mmol). This mixture was purged with nitrogen andthen treated with a catalytic amount of tetrakis(triphenylphosphine)palladium(0) (0.58 g, 0.5 mmol). The reaction was heated to refluxovernight, cooled, acidified with 2N hydrochloric acid and extractedwith ethyl acetate. The organic layer was washed with brine, dried overanhydrous magnesium sulfate, filtered, and evaporated to provide anearly quantitative amount of the title acid which was used in the nextstep without further purification.

[0439] Step C.10-{[6-Chloro-3-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine

[0440] A stirred solution of the2-chloro-2′-trifluoromethyl-5-methoxy-[1,1′-biphenyl]-4-carboxylic acidof Step B (3.46 g, 10.46 mmol) in tetrahydrofuran (20 mL) containing acatalytic amount of N,N-dimethylformamide was treated dropwise withthionyl chloride (1.36 g, 11.51 mmol). The reaction mixture was stirredfor 2 hours, and then added dropwise to a solution of10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (1.92 g 10.46 mmol)in tetrahydrofuran (20 mL) containing triethylamine (2.32 g, 23 mmol).The reaction mixture was stirred for 2 hours, diluted withdichloromethane and washed with saturated aqueous sodium bicarbonate andbrine. The organic layer was dried over anhydrous magnesium sulfate,filtered, and evaporated to dryness. Trituration of the residue withacetone gave 3.14 g of the title compound. Recrystallization fromacetone/hexane provided white crystals, m.p. 208-210° C.;

[0441]¹H NMR (DMSO-d₆, 400 MHz) δ 3.46 (s, 3H), 5.16-5.20 (br, d, 3H),5.89 (t, 1H), 5.97 (s, 1H), 6.70 (s, 1H), 6.80 (t, 1H), 7.80-7.00 (m,10H).

[0442] MS [(+) ESI, m/z]: 497 [M+H]⁺.

[0443] Anal. Calcd. for C₂₇H₂₀ClF₃N₂O₂+0.5H₂O: C 64.10, H 4.18, N 5.54.Found: C 64.40, H 3.97, N 5.54.

[0444] Step D.10-{[6-Chloro-3-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicAcid

[0445] A solution of the10-{[6-chloro-3-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepineof Step C (2.29 g, 4.6 mmol) in dichloromethane (30 mL) was treated withN,N-diisopropylethyl amine (0.62 g, 4.84 mmol) and stirred for 10minutes. Trichloroacetyl chloride (0.92 g, 5.07 mmol) was then addeddropwise. The reaction mixture was stirred overnight, diluted withdichloromethane, washed with 0.1N hydrochloric acid, saturated aqueoussodium bicarbonate, and brine. The organic phase was dried overanhydrous magnesium sulfate, filtered, and evaporated to yield the crudetrichloroketone intermediate which without further purification, wasdissolved in acetone and treated with an excess of 1N sodium hydroxide.The mixture was stirred overnight, and then diluted with isopropylacetate and acidified with 1N hydrochloric acid. The organic layer waswashed with brine, dried over anhydrous magnesium sulfate, filtered, andevaporated to dryness. The solid residue was triturated with methanol toprovide the title compound (1.23 g ) as a white solid, m.p. 220-222° C.(dec).

[0446]¹H NMR (DMSO-d₆, 400 MHz) δ 3.40 (s, 3H), 6.12 (d, 1H), 6.68 (s,1H), 6.72 (d, 1H), 6.94 (s, 2H), 7.07 (t, 1H), 7.25 (d, 2H), 7.62 (t,2H), 7.70 (t, 1H), 7.78 (d, 1H), 12.31 (br, 1H).

[0447] MS [(+)APCI, m/z]: 541 [M+H]⁺.

[0448] Anal. Calcd. for C₂₈H₂₀ClF₃N₂O₄+0.25H₂O: C 61.66, H 3.79, N 5.14.Found: C 61.47, H 3.64, N 5.06.

[0449] Step E.10-{[6-Chloro-3-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-methyl-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0450] To a stirred solution of the10-{[6-chloro-3-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid of Step D (0.250 g, 0.46 mmol) in N.N-dimethylformamide (2 mL) wasadded N-methyl-D-glucamine (0.109 mg, 0.55 mmol), 1-hydroxybenzotriazole(0.069 g, 0.51 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (0.087 g, 0.51 mmol), and N,N-diisopropylethyl amine(0.090 g, 0.69 mmol). After stirring overnight, the reaction mixture wastaken up in chloroform, washed with saturated aqueous sodium bicarbonateand brine, dried over magnesium sulfate, filtered and evaporated.Purification of the residue by flash chromatography eluting with 10%methanol in chloroform provided the title compound (0.132 g ) as anoff-white solid, 96.08% pure by analytical HPLC [Primesphere C-18 column(2.0×150 mm); mobile phase: 45/55 acetonitrile/water containing 0.1%phosphoric acid].

[0451]¹H NMR (DMSO-d₆, 400 MHz) δ 3.05 (br, 3H), 4.33-4.38 (br m, 3H),4.50 (s, 1H), 4.90 (s, 1H), 5.30 (s, 2H), 6.04 (s, 1H), 6.33 (s, 1H),6.68 (s, 1H), 6.94-7.80 (m, 10H).

[0452] MS [(+)ESI, m/z]: 718 [M+H]⁺.

[0453] Anal. Calcd for C₃₅H₃₅ClF₃N₃O₈: C 58.54, H 4.91, N 5.85. Found: C58.29, H 4.48, N 5.42.

EXAMPLE 21

[0454]N-(2,3-Dihydroxypropyl)-10-{[2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0455] Step A. Trifluoromethanesulfonic acid 4-formyl-2-methoxy-phenylester To a solution of vanillin (6.08 g, 40.0 mmol) and triethylamine(6.70 mL, 48.0 mmol) in dichloromethane (300 mL) was added dropwise asolution of trifluoromethanesulfonic anhydride (12.4 g, 44.0 mmol) indichloromethane (100 mL) at 0° C. After stirring for 2 hours, thesolution was concentrated, and the residue washed with water andextracted twice with ethyl acetate. Upon drying and concentrating, theresidual dark oil was subjected to flash chromatography on silica geleluting with 20% ethyl acetate in hexane providing the title product(8.91 g) as a light yellow oil, which was used in the next step withoutfurther purification.

[0456] Step B.2-Methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-carboxaldehyde

[0457] A stirred solution of trifluoromethanesulfonic acid4-formyl-2-methoxy-phenyl ester of Step A (6.9 g, 22.1 mmol),2-trifluoromethyl phenyl boronic acid (5.4 g, 28.6 mmol) and potassiumphosphate (13.2 g, 62.2 mmol) in N,N-dimethylformamide (120 mL) wasdegassed with nitrogen, whereupon a catalytic amount (0.285 g) of[1,4-bis-(diphenylphosphine)butane]palladium (II) dichloride was added.The solution was heated to 120° C. for 5 hours, poured into water andextracted with ethyl acetate. The combined extracts were washed withwater, dried over anhydrous magnesium sulfate and filtered through aplug of silica gel. Removal of the solvent provided the crude titlecompound (4.54 g) as an oil, which was used as such in the next step.

[0458]¹H NMR (200 MHz, CDCl₃): δ 3.91 (s, 3H). (s, 1H), 7.31-7.56 (m,6H), 8.14 (d, 1H), 10.03 (s, 1H).

[0459] Step C. 3-Methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-carboxylicAcid

[0460] The 3-methoxy2′-trifluoromethyl-[1,1′-biphenyl]-4-carboxaldehydeof Step B (0.95 g, 3.41 mmol) and sulfamic acid (0.43 g, 4.43 mmol) weredissolved in a mixture of tetrahydrofuran and water (1:1, v/v, 30 mL).Sodium chlorite (0.31 g, 4.43 mmol) was added under stirring, and thesolution turned yellow. After 30 minutes, additional sodium chlorite andsulfamic acid were added, and the solution stirred an additional hour.The solution was then concentrated, and the residue partitioned betweenethyl acetate and water. The ethyl acetate layer was dried andconcentrated to yield an oil, which solidified upon trituration withhexane to provide the title compound (0.84 g) as a yellow solid, whichwas used as such in the next step.

[0461] Step D.(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)-methanone

[0462] The 3-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-carboxylicacid of Step C (1.6 g, 5.40 mmol) was added to a flask containingtoluene (30 mL), thionyl chloride (1.4 mL) and one drop ofN,N-dimethylformamide. The solution was stirred at 70° C. for 1 hour andthen concentrated in vacuo. The residue was diluted with dichloromethane(40 mL) and to this solution was added10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.94 g, 5.16 mmol).After the solution became homogeneous, N,N-diisopropylethyl amine (1.07mL, 6.19 mmol) was added in one portion at 0° C. After 30 minutes thesolution was concentrated, and the residue partitioned between water andethyl acetate. The ethyl acetate was dried and concentrated to give acrude oil, which was chromatographed on silica gel eluting with 30%ethyl acetate in hexane to yield 1.2 g of product. The solid wasrecrystallized from ethyl acetate/hexane to provide the desired titleproduct (0.87 g) as colorless crystals, m.p. 146-148° C.

[0463]¹H NMR (400 MHz, DMSO-d₆) δ 3.45 (s, 3H), 5.31 (br, 4H), 5.91 (s,1H), 5.95 (br, 1H), 6.83 (s, 1H), 6.92-7.01 (m, 4H), 7.11 (t, 1H), 7.19(m, 2H), 7.46 (d, 1H), 7.53 (t, 1H), 7.62 (t, 1H), 7.72 (d, 1H ).

[0464] MS [(+)ESI, m/z]: 463 [M+H]⁺.

[0465] Anal. Calcd. for C₂₇H₂₁F₃N₂O₂: C 70.12, H 4.58, N 6.06. Found: C70.53, H 4.72, N 5.89.

[0466] Step E.10-{[2-Methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic Acid

[0467] To a stirred solution of the(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)-methanone ofStep D (2.34 g, 5.0 mmol) and N,N-diisopropylethyl amine (1.04 mL, 6.0mmol) in dichloromethane (100 mL) was added dropwise a solution oftrichloroacetyl chloride (1.09 g, 6.0 mmol) in dichloromethane (20 mL)kept at 0° C. After the addition was complete, the solution was stirredovernight at room temperature, then washed with 10% aqueous potassiumcarbonate. The organic phase was dried and concentrated to yield a darkresidue. The residue was purified by filtration through a plug of silicagel, eluting with 20% ethyl acetate in hexane. The resulting tan coloredproduct was dissolved in acetone and 1 N sodium hydroxide (2:1, v/v) andthe mixture was stirred for 30 minutes. The solution was thenconcentrated and extracted with ethyl acetate. The combined organicphases were dried and concentrated to yield a yellow oil. The oil wastriturated with hexane, and the resulting off-white solid was removed byfiltration and dried in vacuo to yield the title compound (1.86 g).

[0468] Step F.N-(2,3-Dihydroxypropyl)-10-{[2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0469] To a stirred solution of the10-{[2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid of Step E (0.300 g, 0.65 mmol)) in N,N-dimethylformamide (15 mL)was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(0.150 g, 0.78 mmol) and 1-hydroxybenzotriazole (0.110 g, 0.78 mmol).After the solution became homogeneous 3-methylamino-1,2-propanediol(0.082 g, 0.78 mmol) was added, and the solution was stirred at roomtemperature overnight. The mixture was then poured into water andextracted with ethyl acetate. The combined ethyl acetate layers werewashed with water, dried and concentrated to dryness. The residue wassubjected to silica chromatography eluting with 10% methanol inchloroform. The pure fractions were concentrated and the residueazeotroped and triturated several times with hexane to provide the titleproduct (0.118 g) as a white solid, m.p. 119-123° C.

[0470]¹H NMR (400 MHz, DMSO-d₆): δ 3.08 (br, 3H), 3.51-3.48 (m, 5H),3.80 (br, 1H), 4.62 (t, 1H), 4.85 (br, 1H), 5.42 (br, 2H), 6.04 (s, 1H),6.34 (s, 1H), 6.85-6.973 (m, 4H), 7.06 (t, 1H), 7.11 (t, 1H), 7.19 (d,1H), 7.40 (d, 1H), 7.56 (t, 1H), (d, 1H), 7.62 (t, 1H ), 7.74 (d, 1H).

[0471] MS [El , m/z]: 593 [M]⁺.

[0472] Anal. Calcd. for C₃₂H₃₀F₃N₃O₅: C 64.75, H 5.09, N 7.08. Found: C63.51, H 4.63, N 6.98.

EXAMPLE 22

[0473]N-[(3-Dimethylamino)-2-hydroxy-propyl]-10-{[2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0474] The title compound was obtained from10-{[2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid of Example 21, Step E (0.15 g, 0.32 mmol) andN,N,N′-trimethyl-2-hydroxy-propane diamine (0.065 g, 0.32 mmol.) in themanner of Example 21, Step F, as a white solid (0.093 g), m.p. 120-125(dec.).

[0475]¹H NMR (400 MHz, DMSO-d₆): δ 7.74 (d, 1H), 7.62 (t, 1H), 7.56 (t,1H), 7.40 (d, 1H), 7.19 (d, 1H), 7.11 (t, 1H), 7.06 (t, 1H), 6.85-6.97(m, 4H), 6.34 (s, 1H), 6.04 (s, 1H), 5.40 (br, 2H), 5.10 (br, 1H), 4.84(br, 1H), 3.91 (br, 1H), 3.59 (br, 1H), 3.41 (s, 3H), 3.15 (br, 3H),2.19 (br, 6H).

[0476] MS [El, m/z]: 620 [M]⁺.

[0477] Anal. Calcd. for C₃₄H₃₅F₃N₄O₄: C 65.8, H 5.69, N 9.03. Found: C65.39, H 6.02, N 8.56.

EXAMPLE 23

[0478]10-{[2-Methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-methyl-N-[(2R,3S,4R,5S)-2,3,4,5,6-pentahydroxyhexyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0479] The title compound was obtained from10-{[2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid of Example 21, Step E (0.15 g, 0.32 mmol) and1-deoxy-1-(methylamino)-D-galactitol (0.063 g, 0.32 mmol) in the mannerof Example 21, Step F, as a white solid (0.078 g), m.p. 132-140° C.(dec).

[0480]¹H NMR (400 MHz, DMSO-d₆): δ 3.06 (br, 3H), 3.25-3.51 (m, 5H), d,1H), 3.71 (m, 1H), 4.06 (d, 1H), 4.15 (d, 1H), 4.23 (br, 1H), 4.42 (t,1H), 5.42 (br, 2H), 6.06 (s, 1H), 6.38 (s, 1H), 6.85-6.973 (m, 4H), 7.04(t, 1H), 7.11 (t, 1H), 7.19 (d, 1H), 7.42 (d, 1H), 7.56 (t, 1H), 7.62(t, 1H ).

[0481] MS [El, m/z]: 683 [M]⁺.

[0482] Anal. Calcd. for C₃₅H₃₆F₃N₃O₈: C 61.49, H 5.31, N 6.15. Found: C60.38, H 4.88, N 5.88.

EXAMPLE 24

[0483]10-[4-(Naphthalen-1-yl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid bis-(2-hydroxy-ethyl)-amide

[0484] Step A. 4-Naphthalen-1-yl-benzoic Acid Methyl Ester

[0485] Methyl 4-bromobenzoate (0.96 g, 4.46 mmol) was added to a mixtureof 1-naphthaleneboronic acid (0.73 g, 4.25 mmol) and sodium carbonate(0.075 g, 7.08 mmol) in toluene (30 mL), ethanol (6 mL) and water (12mL). The resultant solution was purged with nitrogen for 10 minutesbefore tetrakis(triphenylphosphine) palladium(0) (0.10 g, 0.09 mmol) wasadded. The reaction mixture was heated to reflux for 65 hours. Thesolution was cooled to ambient temperature, then filtered through a padof Celite, which was subsequently rinsed with ethyl acetate. Thecombined filtrate was diluted to 100 mL with water/ethyl acetate (1:1,v/v). The aqueous layer was extracted with ethyl acetate, and thecombined extracts were dried over anhydrous magnesium sulfate, filtered,and evaporated to dryness to yield the title compound as a gold oil(1.09 g). This material was used without further purification in thenext step.

[0486]¹H NMR (300 MHz, DMSO-d₆): δ 8.10 (d, 2H), 8.02 (t, 2H), 7.75 (d,1H), 7.57 (m, 6H), 3.92 (s, 3H).

[0487] Step B. 4-Naphthalen-1-yl-benzoic Acid

[0488] To a stirred solution of the 4-naphthalen-1-yl-benzoic acidmethyl ester of Step A (1.09 g, 4.15 mmol), in methanol (18 mL) andwater (6 mL), cooled to 5° C., was added lithium hydroxide monohydrate(0.42 g, 10.0 mmol). The solution was allowed to warm to ambienttemperature as stirring was continued for 20 hours. The reaction mixturewas poured into water, acidified to pH 4 with acetic acid, and theresultant precipitate was isolated by vacuum filtration to afford thetitle compound as an off-white solid (0.92 g), m.p. 221-224° C.

[0489]¹H NMR (400 MHz, DMSO-d₆): δ 6.40-7.60 (m, 7H),. 7.56 (d, 1H),7.98 (d, 1H), 8.01 (d, 1H), 8.07 (d, 2H).

[0490] MS [El, m/z]: 248 [M]⁺.

[0491] Anal. Calc'd. for C₁₇H₁₂O₂: C 82.24, H 4.87. Found: C 81.90, H4.63.

[0492] Step C.[4-(Naphtalen-1-yl)phenyl][10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone

[0493] N,N-Dimethylformamide (2 drops) was added to a solution of the4-naphthalen -1-yl-benzoic acid of Step B (0.60 g, 2.40 mmol) inanhydrous tetrahydrofuran (15 mL). Oxalyl chloride (0.34 g, 2.64 mmol)was added and the mixture was warmed to reflux. The resultant solutionwas cooled to ambient temperature before being evaporated to dryness togive the crude acid chloride as a gold solid, which was used withoutfurther purification. To a mixture of10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.37 g, 2.00 mmol)and triethylamine (0.24 g, 2.40 mmol) in dichloromethane (5 mL), cooledin an ice bath, was added dropwise a solution of the crude acid chloridein dichloromethane (5 mL). The cooling bath was removed and afterstirring for 48 hours, the reaction mixture was washed sequentially withwater, saturated aqueous sodium bicarbonate, saturated aqueous sodiumchloride and 1 N sodium hydroxide. The dichloromethane solution wasdried with anhydrous magnesium sulfate, filtered, then evaporated todryness to yield a brown foam. Purification by flash chromatography onsilica gel eluting with hexane-ethyl acetate (4:1) resulted in a whitefoam (0.47 g). Treatment of the white foam with diethyl ether andsonication resulted in a white solid (0.37 g), m.p. 169.5-171° C.

[0494]¹H NMR (400 MHz, DMSO-d₆): δ 5.32 (br, 4H), 5.93 (m, 1H), 5.97 (s,1H), 6.83 (m, 1H), 7.01 (d, 1H), 7.18 (m, 2H), 7.32 (t, 2H), 7.41, (d,1H), 6.45-7.60 (m, 5H), 7.93 (d, 1H), 7.97 (d, 1H).

[0495] MS [El, m/z]: 414 [M]⁺.

[0496] Anal. Calcd. for C₂₉H₂₂N₂O+0.4H₂O: C 82.60, H 5.45, N 6.64.Found: C 82.71, H 5.44, N 6.54.

[0497] Step D.10-[4-(Naphthalen-1-yl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicAcid

[0498] Prepared by treatment of[4-(naphthalen-1-yl)phenyl][10,11-dihydro-5H-pyrrolo[2,1c][1,4]benzodiazepin-10-yl]-methanoneof Step C with trichloroacetyl chloride, followed by basic hydrolysis ofthe intermediate trichloroacetate ester in the manner of Example 1, StepF.

[0499] Step E.10-[4-(Naphthalen-1-yl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicAcid bis-(2-hydroxy-ethyl)-amide

[0500] The title compound was prepared by coupling the10-[4-(naphthalen-1-yl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid of Step D, with diethanolamine (1.25 equiv) in the manner ofExample 1, Step G.

EXAMPLE 25

[0501]2-{4-[10-{[2-Chloro-4-(naphthalen-1-yl)phenyl]carbonyl}-(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)carbonyl]piperazine-1-yl}-1-hydroxyethane

[0502] Step A.(4-Bromo-2-chloro-benzoyl)-(10,11H-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone

[0503] N,N-Dimethylformamide (1 drop) was added to a solution of4-bromo-2-chlorobenzoic acid (2.20 g, 9.35 mmol) in anhydroustetrahydrofuran (20 mL). Oxalyl chloride (1.46 g, 11.46 mmol) was addedand the mixture was warmed to reflux. The resultant solution was cooledto ambient temperature before being evaporated to dryness to give thecrude acid chloride as a gold viscous liquid, which was used withoutfurther purification. To a mixture of10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (1.44 g, 7.79 mmol)and triethylamine (0.95 g, 9.35 mmol) in dichloromethane (40 mL), cooledin an ice bath, was added dropwise a solution of the acid chloride indichloromethane (20 mL). The cooling bath was removed and after stirringfor 22 hours, the reaction mixture was washed sequentially with water,saturated aqueous sodium bicarbonate, 0.5 N hydrochloric acid and water.The dichloromethane solution was dried over anhydrous sodium sulfate,filtered, then evaporated to dryness to yield an off-white foam.Purification by flash chromatography on silica gel eluting withhexane-ethyl acetate (2:1) resulted in a white foam (3.02 g), m.p.77-80° C. This material was used as such in the next step.

[0504]¹H NMR (400 MHz, DMSO-d₆): δ 5.45 (br, 4H), 7.02 (t, 1H), 7.07(td, 1H), 7.14 (td, 1H), 7.32 (br, 1H), 7.38 (d, 2H), 7.68 (br ,1H).

[0505] MS [El, m/z]: 400 [M]⁺.

[0506] Step B.[2-Chloro-4-naphthalen-1-yl-phenyl)-(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone

[0507] 1-Naphthaleneboronic acid (0.52 g, 3.00 mmol) was added to amixture of(4-bromo-2-chloro-benzoyl)-(10,11-dihydro-5H—pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanoneof Step A (1.27 g, 3.15 mmol) and sodium carbonate (0.53 g, 4.98 mmol)in toluene (22.5 mL), ethanol (4.5 mL) and water (9 mL). The resultantsolution was purged with nitrogen for 10 minutes, thentetrakis(triphenylphosphine) palladium (0.18 g, 0.06 mmol) was added.The reaction mixture was heated to reflux for 76 hours, cooled toambient temperature, then filtered through a pad of Celite, which wassubsequently rinsed with ethyl acetate. The combined filtrate wasdiluted to 100 mL water/ethyl acetate (1:1). The aqueous layer wasextracted with ethyl acetate, and the combined organic layer was driedover anhydrous magnesium sulfate, filtered, and evaporated to dryness toyield a brown oil. Purification by flash chromatography on silica geleluting with hexane-ethyl acetate (5:1) resulted in a white solid whichwas dried under vacuum (0.62 g), m.p. 115-117.5° C.

[0508]¹H NMR (400 MHz, DMSO-d₆): δ 5.91 (t, 1H), 6.02 (br, 1H), 6.84(br, 1H), 7.14 (m, 2H), 7.24 (d, 1H), 7.34, (d, 1H), 7.95 (d, 1H), 7.98(d, 1H).

[0509] MS [(+)ESI, m/z]: 449 [M+H]⁺.

[0510] Anal. Calcd. for C₂₉H₂₁ClN₂O+0.25H₂O: C 76.72, H 4.79, N 6.17.Found C 76.72, H 4.53, N 5.95.

[0511] Step C.10-{[2-Chloro-4-(naphthalen-1-yl)phenyl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicAcid

[0512] Prepared by treatment of[2-chloro-4-(naphthalen-1-yl)-phenyl]-(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone of Step B withtrichloroacetyl chloride, followed by basic hydrolysis of theintermediate trichloroacetate ester in the manner of Example 1, Steps Eand F.

[0513] Step D.2-{4-[10-{[2-Chloro-4-(naphthalen-1-yl)phenyl]carbonyl}-(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)carbonyl]piperazine-1-yl}-1-hydroxy-ethane

[0514] The title compound was prepared from10-{[2-chloro-4-(naphthalen-1-yl)phenyl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid of Step C and 1-(2-hydroxyethyl)-piperazine in the manner ofExample 1, Step G.

[0515] HRMS [(+)ESI, m/z]: 605.23105 [M+H]⁺. Calcd. for C₃₆H₃₄ClN₄O₃605.23140.

EXAMPLE 26

[0516]10-{[4-(4-Methyl-naphthalen-1-yl)phenyl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid (2,3-dihydroxy-propyl)-N-methylamide

[0517] Step A. 4-(4-Methyl)-napthalen-1-yl-benzoic Acid

[0518] To a mixture of 1-bromo-4-methyl napthalene (1.11 g, 5.00 mmol)and 4-carboxyphenyl boronic acid (1.00 g, 6.00 mmol) in ethylene glycoldimethyl ether (20 mL) was added a solution of sodium carbonate (2.37 g,22.38 mmol) in water (18.75 mL). The resultant mixture was purged withnitrogen for 20 minutes before tetrakis(triphenylphosphine)palladium(0)(0.03 g, 0.02 mmol) was added. The reaction mixture was heated to refluxfor 68 hours. After the solution cooled to ambient temperature, thesolvent was removed in vacuo and the residue was acidified with 5 Nhydrochloric acid to produce and orange-brown solid that was isolated byvacuum filtration. This material was used without further purificationin the next step.

[0519]¹H NMR (300 MHz, DMSO-d₆): δ 2.70 (s, 3H), 7.57 (d, 2H), 8.07 (d,2H).

[0520] Step B.[4-(4-Methyl-naphthalen-1-yl)phenyl][10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]methanone

[0521] N,N-Dimethylformamide (2 drops) was added to a solution of4-(4-methyl)-napthalen -1-yl-benzoic acid of Step A (0.90 g, 3.43 mmol),in anhydrous tetrahydrofuran (10 mL). Oxalyl chloride (0.52 g, 4.12mmol) was added and the mixture was warmed to reflux. The resultantsolution was cooled to ambient temperature before being evaporated todryness to give the crude acid chloride as a brown residue, which wasused without further purification. To a mixture of10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.53 g, 2.86 mmol)and triethylamine (0.35 g, 3.43 mmol) in dichloromethane (10 mL), cooledin an ice bath, was added dropwise a solution of the crude acid chloridein dichloromethane (10 mL). The cooling bath was removed and afterstirring for 137 hours, the reaction mixture was washed sequentiallywith water, saturated aqueous sodium bicarbonate, and saturated aqueoussodium chloride. The dichloromethane solution was dried over anhydrousmagnesium sulfate, filtered, then evaporated to dryness to yield anamber oil. Purification by flash chromatography on silica gel elutingwith hexane-ethyl acetate (4:1) resulted in a tan foam (0.49 g).Treatment of this material with diethyl ether and sonication resulted inan off-white solid (0.37 g), m.p. 160-162° C.

[0522]¹H NMR (400 MHz, DMSO-d₆): δ 2.66 (s, 3H), 5.32 (br, 4H), 5.93 (t,1H), 5.97 (br, 1H), 6.83 (t, 1H), 7.01 (d, 1H), 7.22 (d, 2H), 7.28 (d,2H), 7.39 (t, 3H), 7.45 (m, 2H), 7.57 (m, 2H), 8.06 (d, 1H).

[0523] MS [(+)ESI, m/z]: 429 [M+H]⁺.

[0524] Anal. Calcd. for C₃₀H₂₄N₂O+0.13H₂O: C 83.63, H 5.67, N 6.50.Found: C 83.63, H 5.64, N 6.43

[0525] Step C.10-{[4-(4-Methyl-naphthalen-1-yl)phenyl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicAcid

[0526] Prepared from[4-(4-methyl-naphthalen-1-yl)-phenyl]-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-10-yl]methanoneof Step B by treatment with trichloroacetyl chloride, followed by basichydrolysis of the intermediate trichloroacetate ester in the manner ofExample 1, Steps E and F.

[0527] Step D.10-{[4-(4-Methyl-naphthalen-1-yl)phenyl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicAcid (2,3-dihydroxy-propyl)—N-methylamide

[0528] Prepared by the coupling of the10-{[4-(4-methyl-naphthalen-1-yl)phenyl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid of Step C, with 3-methylamino-1,2-propanediol (1.2 equiv.) in themanner of Example 2.

EXAMPLE 27

[0529]10-[(3-Methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid methyl-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]-amide

[0530] Step A. 4-Iodo-2-methoxybenzoic Acid Methyl Ester

[0531] 4-Amino-2-methoxybenzoic acid methyl ester (3.0 g, 16.6 mmol) wassuspended in water (40 mL) and concentrated sulfuric acid (10 mL). Thesuspension was cooled in an ice/salt water bath, and an aqueous solution(10 mL) of sodium nitrite (1.26 g, 18.3 mmol) was added dropwise so thatthe temperature remained close to 0° C. After the addition, ahomogeneous, yellow-green solution was obtained. An aqueous solution (60mL) of potassium iodide (3.02 g, 18.2 mmol) and iodine (2.31 g, 9.1mmol) was then added dropwise, and the reaction stirred for anadditional 1 hour. The reaction mixture was then extracted with ethylacetate, the organic extracts were combined and washed with 1 N sodiumthiosulfate, 1 N sodium hydroxide and brine. After drying over anhydroussodium sulfate the solution was filtered and concentrated in vacuo togive 2.7 g of the title product as an orange oil which was used in thenext step.

[0532]¹H NMR (DMSO-d₆, 400 MHz): δ 2.76 (s, 3H), 3.82 (s, 3H), 7.39 (s,2H), 7.48 (s, 1H).

[0533] MS [El, m/z]: 292 [M]⁺.

[0534] Step B. 4-lodo-2-methoxybenzoic Acid

[0535] The 4-iodo-2-methoxybenzoic acid methyl ester of Step A (2.7 g,9.24 mmol) was dissolved in tetrahydrofuran (40 mL) and 1 N sodiumhydroxide (20 mL, 20 mmol) was added. The reaction mixture was heated atreflux for 3 hours, then cooled and concentrated in vacuo to give anorange oil that was partitioned between ethyl acetate and 2 Nhydrochloric acid. The organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo to give 2.5 g of titleproduct as a yellow-orange solid, m.p. 144-146° C.

[0536]¹H NMR (DMSO-d₆, 400 MHz): δ 3.81 (s, 3H), 7.37 (s, 2H), 7.44 (s,1H), 12.72 (br, 1H).

[0537] MS [El, m/z]: 278 [M]⁺.

[0538] Anal. Calcd. for C₈H₇₁₀ ₃+0.10 C₄H₈O₂: C 35.17, H 2.74. Found: C35.37, H 2.49.

[0539] Step C.10-(4-Iodo-2-methoxybenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine

[0540] A suspension of 4-iodo-2-methoxybenzoic acid of Step B (2.5 g,9.0 mmol) in thionyl chloride (10 mL) was heated at reflux for 1 hour.After cooling, the thionyl chloride was removed in vacuo. The residuewas dissolved in toluene and concentrated in vacuo to give the crudeacid chloride as a brown solid. The acid chloride was then dissolved indichloromethane (10 mL) and slowly added to a solution of10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (1.75 g, 9.5 mmol)and N,N-diisopropylethyl amine (3.4 mL, 19.5 mmol) in dichloromethane(20 mL). After stirring for 2 hours, the reaction was quenched withwater. The organic layer was washed with 1 N hydrochloric acid, 1 Nsodium hydroxide and brine, dried over anhydrous sodium sulfate,filtered and concentrated in vacuo to give a yellow foam. Purificationby flash chromatography on silica gel using a solvent gradient of 15 to25% ethyl acetate in hexane provided 3.6 g of title product as a whitefoam, which was redissolved in dichloromethane and evaporated to drynessprior to use in the next step.

[0541]¹H NMR (DMSO-d₆, 400 MHz): δ 3.55 (br, 3H), 4.80-5.32 (br, 4H),5.88-5.90 (m, 1H), 5.94 (s, 1H), 6.79 (s, 1H), 6.94 (s, 1H), 7.03 (t,1H), 7.09-7.13 (m, 3H), 7.20-7.22 (m, 1H), 7.36-7.38 (m, 1H).

[0542] MS [(+)ESI, m/z]: 445 [M+H]⁺.

[0543] Anal. Calcd. for C₂₀H₁₇1N₂O₂+0.10 C₄H₈O₂+0.13 CH₂Cl₂: C 53.13, H3.92, N 6.04. Found: C 53.03, H 3.65, N 6.03.

[0544] Step D.(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl]-methanone

[0545] A mixture of10-(4-iodo-2-methoxybenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepineof Step C (1.8 g, 4.1 mmol), 2-methylphenyl boronic acid (0.55 g, 4.1mmol) and sodium carbonate (1.9 g, 17.9 mmol) in toluene:ethanol: water(20 mL:10 mL:10 mL) was purged with nitrogen for 1 hour. After additionof the tetrakis(triphenylphosphine) palladium(0) catalyst (0.24 g, 0.21mmol), the reaction mixture was heated at 100° C. overnight. Aftercooling, the reaction was filtered through Celite and the cake washedwith ethyl acetate. The organic layer was washed with water, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to give abrown oil. Purification by flash chromatography on silica gel using asolvent system of 20% ethyl acetate in hexane provided 1.5 g of titleproduct as a white foam, which was redissolved in dichloromethane andevaporated to dryness in vacuo prior to use in the next step.

[0546]¹H NMR (DMSO-d₆, 400 MHz): δ 2.08 (s, 3H), 3.54 (s, 3H), 4.80-5.30(br, 4H), 5.89-5.91 (m, 1H), 5.97 (s, 1H), 6.66 (s, 1H), 6.77-6.80 (m,2H), 6.93-7.01 (m, 2H), 7.09-7.10 (m, 2H), 7.19-7.24 (m, 3H), 7.36-7.38(m, 2H).

[0547] MS [(+)ESI, m/z]: 409 [M+H]⁺.

[0548] Anal. Calcd. for C₂₇H₂₄N₂O₂+0.10 CH₂Cl₂: C 78.05, H 5.84, N 6.72.Found: C 78.12, H 5.13, N 6.69.

[0549] Step E.2,2,2-Trichloro-1-{10-[(3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone

[0550] To a solution of(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl]-methanoneof Step D (1.36 g, 3.33 mmol) in dichloromethane (15 mL) was addedN,N-diisopropylethyl amine (1.2 mL, 6.89 mmol) followed by slow additionof trichloroacetyl chloride (1.1 mL, 9.85 mmol). The reaction mixturewas stirred overnight at room temperature then was quenched with water.The organic phase was washed with 0.1 N hydrochloric acid followed bywater, then dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give a green oil. Purification by flashchromatography on silica gel using a solvent system of 20% ethyl acetatein hexane gave 1.7 g of title product as a yellow foam.

[0551]¹H NMR (DMSO-d₆, 400 MHz): δ 2.09 (s, 3H), 3.50 (s, 3H), 5.30 (br,2H), 5.87 (br, 2H), 6.37-6.38 (m, 1H), 6.64 (s, 1H), 6.82-6.83 (m, 1H),6.90-6.92 (m, 1H), 6.97-6.99 (m, 1H), 7.10-7.12 (m, 2H), 7.20-7.25 (m,4H), 7.35-7.37 (m, 1H), 7.44-7.46 (m, 1H).

[0552] MS [(+)APCI, m/z]: 553 [M+H]⁺.

[0553] Anal. Calcd. for C₂₉H₂₃C₁₃N₂O₃+0.20 C₄H₈O₂+0.40H₂O: C 61.85, H4.42, N 4.84. Found: C 61.50, H 4.07, N 4.72.

[0554] Step F.10-[(3-Methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicAcid

[0555] To a solution of2,2,2-trichloro-1-{10-[(3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanoneof Step E (1.6 g, 2.9 mmol) in acetone (20 mL) was added 2.5 N sodiumhydroxide (2.3 mL, 5.8 mmol). After stirring overnight, the reaction wasacidified with 2 N hydrochloric acid (3.2 mL, 6.4 mmol) thenconcentrated in vacuo. The residue was partitioned between ethyl acetateand water. The layers were separated, and the organic layer was driedover anhydrous sodium sulfate, filtered and concentrated in vacuo togive a brown solid. Trituration with diethyl ether/hexane provided 1.2 gof desired product as an off-white solid, m.p. 201-204° C.

[0556]¹H NMR (DMSO-d₆, 400 MHz): δ 2.09 (s, 3H), 3.48 (s, 3H), 5.20 (br,2H), 5.85 (br, 2H), 6.12 (s, 1H), 6.62 (s, 1H), 6.73 (d, 1H), 6.79-6.87(m, 2H), 6.91-6.95 (m, 1H), 6.99-7.03 (m, 1H), 7.06-7.12 (m, 1H),7.18-7.25 (m, 4H), 7.39 (br, 1H), 12.31 (br, 1H).

[0557] MS [(+) ESI, m/z]: 453 [M+Na]⁺.

[0558] Anal. Calcd. for C₂₈H₂₄N₂O₄+0.10 C₄H₁₀0 +0.15 C₄H₈O₂: C 73.61, H5.58, N 5.92. Found: C 73.23, H 5.49, N 6.06.

[0559] Step G.10-[(3-Methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicAcid methyl-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy-hexyl]-amide

[0560] To a solution of10-[(3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid of Step F, N-methyl-D-glucamine and 1-hydroxybenzotriazole inN,N-dimethylformamide was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride followed by N,N-diisopropylethylamine in themanner of Example 17. The reaction mixture was stirred overnight, thendiluted with ethyl acetate and washed with water and saturated aqueoussodium bicarbonate. The organic phase was then dried over anhydroussodium sulfate, filtered and concentrated in vacuo to give a yellowfoam. Purification by flash chromatography on silica gel using a solventsystem of 5% methanol in dichloromethane afforded the title compound asa white foam.

EXAMPLE 28

[0561]{10-[(2′-Chloro-6-chloro-3-methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-yl}[(2S,5S)-bis-hydroxymethyl-(3R, 4R)-bis-hydroxy-pyrrolidin-1-yl]-methanone

[0562] Step A. 2′-Chloro-2-chloro-5-methoxy-[1,1′-biphenyl]-4-carboxylicAcid.

[0563] To a stirred solution of 4-iodo-5-chloro-2-methoxy benzoic acid(3.12 g, 10 mmol) of Example 20, Step A in N,N-dimethylformamide (100mL) was added 2-chlorophenyl boronic acid (5.07 g, 32.4 mmol) andpotassium carbonate (12.73 g, 92 mmol). This mixture was purged withnitrogen and then treated with tetrakis(triphenylphosphine) palladium(0)(0.58 g, 0.5 mmol). The reaction was heated to reflux overnight, cooled,acidified with 2 N hydrochloric acid and extracted with ethyl acetate.The organic layer was washed with brine, dried over anhydrous magnesiumsulfate, filtered, and evaporated to provide a nearly quantitativeamount of the title acid which was used in the next step without furtherpurification.

[0564] Step B.10-{[2′-Chloro-6-chloro-3-methoxy-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine

[0565] A stirred solution of the2′-chloro-2-chloro-5-methoxy-[1,1′-biphenyl]-4-carboxylic acid of Step A(3.09 g, 10.46 mmol) in tetrahydrofuran (20 mL) containing a catalyticamount of N,N-dimethylformamide was treated dropwise with thionylchloride (1.36 g, 11.51 mmol). The reaction mixture was stirred for 2hours, and then added dropwise to a solution of10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (1.92 g 10.46 mmol)in tetrahydrofuran (20 mL) containing triethylamine (2.32 g, 23 mmol).The reaction mixture was stirred for 2 hours, diluted withdichloromethane and washed with saturated aqueous sodium bicarbonate andbrine. The organic layer was dried over anhydrous magnesium sulfate,filtered, and evaporated to dryness. Trituration of the residue withethyl acetate gave the title compound (1.93 g) which was recrystallizedfrom ethyl acetate/hexanes as white crystals, m.p. 209-211° C.;

[0566]¹H NMR (DMSO-d₆, 400 MHz) δ 3.55 (s, 3H), 5.16-5.20 (br m, 3H),5.89 (t, 1H), 5.97 (s, 1H), 6.71 (s, 1H), 6.80 (s, 1H), 7.04-7.60 (m,10H).

[0567] MS [(+) APCI, m/z]: 463 [M+H]⁺.

[0568] Anal. Calcd. for C₂₆H₂₀C₂N₂O₂+0.25 C₄H₈O₂: C 66.81, H 4.57, N5.77. Found: C 66.76, H 4.24, N 5.93.

[0569] Step C.10-{[2′-Chloro-6-chloro-3-methoxy-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicAcid

[0570] A solution of10-{[2′-chloro-6-chloro-3-methoxy-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepineof Step B (2.1 g, 4.6 mmol) in dichloromethane (30 mL) was treated withN,N-diisopropylethyl amine (0.62 g, 4.84 mmol) and stirred for 10minutes. Trichloroacetyl chloride (0.92 g, 5.07 mmol) was then addeddropwise. The reaction mixture was stirred overnight, diluted withdichloromethane, washed with 0.1 N hydrochloric acid, saturated aqueoussodium bicarbonate, and brine. The organic phase was dried overanhydrous magnesium sulfate, filtered, and evaporated to yield the crudetrichloroketone intermediate which without further purification, wasdissolved in acetone and treated with an excess of 1 N sodium hydroxide.The mixture was stirred overnight, diluted with isopropyl acetate andacidified with 1 N hydrochloric acid. The organic layer was washed withbrine, dried over anhydrous magnesium sulfate, filtered, and evaporatedto dryness. The solid residue was triturated with methanol to providethe title compound as a white solid, which was used without furtherpurification.

[0571] Step D.{10-[(2′-Chloro-6-chloro-3-methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-yl}[(2S,5S)-bis-hydroxymethyl-(3R, 4R)-bis-hydroxy-pyrrolidin-1-yl]-methanone

[0572] The title compound was prepared in the manner of Example 1, StepG, by the coupling of the10-{[2′-chloro-6-chloro-3-methoxy-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid of Step C with (2S, 5S)-bis-hydroxymethyl-(3R,4R)-bis-hydroxy-pyrrolidine [prepared in the manner of Bennani et al.,EP 0 558 395 A1 (1993)].

EXAMPLE 29

[0573]10-[(6-Chloro-2′-ethoxy-3-methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid methyl-(2,3,4-trihydroxy-butyl)-amide

[0574] Step A. 2-Chloro-2′-ethoxy-5-methoxy[1,1′-biphenyl]-4-carboxylicAcid

[0575] To a stirred solution of 4-iodo-5-chloro-2-methoxy benzoic acidof Example 15, Step A (0.500 g, 1.6 mmol) in N,N-dimethylformamide (30mL) was added 2-ethoxy phenyl boronic acid (0.8 g, 4.8 mmol) andpotassium carbonate (2.04 g, 14.7 mmol). This mixture was purged withnitrogen and then treated with a catalytic amount oftetrakis(triphenylphosphine) palladium(0) (0.093 g, 0.08 mmol). Thereaction was heated to reflux overnight, cooled, acidified with 2 Nhydrochloric acid and extracted with ethyl acetate. The organic layerwas washed with brine, dried over anhydrous magnesium sulfate, filtered,and evaporated to yield the title acid which was used in the next stepwithout further purification.

[0576] Step B.10-{[6-Chloro-3-methoxy-2′-ethoxy-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine

[0577] To a stirred solution of the2-chloro-2′-ethoxy-5-methoxy[1,1′-biphenyl]-4-carboxylic acid of Step A(0.491 g) in tetrahydrofuran (5 mL) containing a catalytic amount ofN,N-dimethylformamide was added dropwise thionyl chloride (0.210 g, 1.76mmol). The reaction mixture was stirred for 2 hours, and then addeddropwise to a solution of10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.294 g, 1.60 mmol)in tetrahydrofuran (5 mL) containing triethylamine (0.357 g, 3.52 mmol).The reaction mixture was stirred for 2 hours, diluted withdichloromethane and washed with saturated aqueous sodium bicarbonate andbrine. The organic layer was dried over anhydrous magnesium sulfate,filtered, and evaporated to dryness. Trituration of the residue withmethanol provided the title compound as an off-white solid, 99.24% pureby analytical HPLC [Primesphere C-18 column (2.0×150 mm); mobile phase70/30 acetonitrile/water containing 0.1% phosphoric acid], m.p. 213-215°C.

[0578]¹H NMR (DMSO-d₆, 400 MHz): δ 1.11, (t, 3H), 3.51 (s, 3H), 3.92 (q,2H), 5.17-5.20 (br, m, 3H), 5.89 (t, 1H), 5.97 (s, 1H), 6.67-7.55 (m,10H).

[0579] MS [(+)APCI, m/z]: 473 [M+H]⁺.

[0580] Anal. Calcd. for C₂₈H₂₅ClN₂O₃: C 71.11, H 5.33, N 5.92. Found: C70.31, H 5.27, N 5.79.

[0581] Step C.10-{[6-Chloro-3-methoxy-2′-ethoxy[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic Acid

[0582] Prepared by treatment of10-{[6-chloro-3-methoxy-2′-ethoxy-1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepineof Step B with trichloroacetyl chloride, followed by basic hydrolysis ofthe intermediate trichloroacetate ester in the manner of Example 1, StepF.

[0583] Step D.10-[(6-Chloro-2′-ethoxy-3-methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid methyl-(2,3,4-trihydroxy-butyl)-amide

[0584] Obtained by coupling the10-{[6-chloro-3-methoxy-2′-ethoxy[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid of Step C with 4-methylamino-butane-1,2,3-triol [prepared in themanner of Bennani et al., EP 0 558 395 A1 (1993)] (1.25 equiv.) in themanner of Example 2.

EXAMPLE 30

[0585]N-(2,3-Dihydroxy-propyl)-N-(2,3,4-trihydroxy-butyl)-10-{[6-chloro-2′-fluoro-3-methoxy-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0586] Step A. 2-Chloro-2′-fluoro-5-methoxy[1,1′-biphenyl]-4-carboxylicAcid

[0587] To a stirred solution of 4-iodo-5-chloro-2-methoxy benzoic acidof Example 20, Step A (3.72 g, 19.1 mmol) in N,N-dimethylformamide (20mL) was added 2-fluorophenyl boronic acid (5.0 g, 35.7 mmol) andpotassium carbonate (14.8 g, 107 mmol). This mixture was purged withnitrogen and then treated with a catalytic amount oftetrakis(triphenylphosphine) palladium(0) (0.688 g, 0.59 mmol). Thereaction was heated to reflux overnight, cooled, acidified with 2 Nhydrochloric acid and extracted with ethyl acetate. The organic layerwas washed with brine, dried over anhydrous magnesium sulfate, filtered,and evaporated to dryness. The residue was flash chromatographed on acidwashed silica using a 10 to 50% gradient of diethyl ether in hexane toprovide the desired title compound (3.8 g) as a white solid.

[0588]¹H NMR (DMSO-d₆, 400 MHz): δ 3.83 (s, 3H), 7.15 (s, 1H), 7.30-7.35(m, 2H), 7.42 (m, 1H), 7.48-7.54 (m, 1H), 7.74 (s, 1H).

[0589] MS [(+)ESI, m/z]: 298 [M+NH₄]⁺.

[0590] Anal. Calcd. for C₁₄H₁₀ClFO₃: C 59.91, H 3.59. Found: C 59.79, H3.35.

[0591] Step B.10-{[6-Chloro-3-methoxy-2′-fluoro-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine

[0592] To a stirred solution of2-chloro-2′-fluoro-5-methoxy[1,1′-biphenyl]-4-carboxylic acid of Step A(3.80 g, 13.5 mmol) in tetrahydrofuran (20 mL) containing a catalyticamount of N,N-dimethylformamide was added dropwise thionyl chloride(1.77 g, 14.9 mmol). The reaction mixture was stirred for 2 hours, andthen added dropwise to a solution of10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (2.49 g, 13.5 mmol)in tetrahydrofuran (20 mL) containing triethylamine (3.0 g, 29.8 mmol).The reaction mixture was stirred for 2 hours, diluted withdichloromethane and washed with saturated aqueous sodium bicarbonate andbrine. The organic layer was dried over anhydrous magnesium sulfate,filtered, and evaporated to dryness. Recrystallization of the residuefrom ethyl acetate/heptane provided the title compound as a pale yellowsolid, m.p. 192-194° C., found to be 99.99% pure by analytical HPLC[Primesphere C-18 column (2.0×150 mm); mobile phase: gradient from 10 to100% of acetonitrile/water containing 0.1% phosphoric acid, 7 minutegradient].

[0593]¹H NMR (DMSO-d₆, 400 MHz) δ 3.55 (s, 3H), 5.19 (br m, 2H), 5.90(t, 1H), 5.96 (s, 1H), 6.80 (s, 2H), 7.07-7.63 (m, 10H).

[0594] MS [(+)ESI, m/z]: 447 [M+H]⁺.

[0595] Anal. Calcd. for C₂₆H₂₀ClFN₂O₂+H₂O: C 69.60, H 4.54, N 6.24.Found: C 69.39, H 4.41, N 6.20.

[0596] Step C.10-{[6-Chloro-3-methoxy-2′-fluoro-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicAcid

[0597] A solution of the10-{[6-chloro-3-methoxy-2′-fluoro-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepineof Step B (3.02 g, 6.76 mmol) in dichloromethane (35 mL) was treatedwith N,N-diisopropylethyl amine (0.960 g, 7.43 mmol) and stirred for 10minutes. Trichloroacetyl chloride (1.47 g, 8.10 mmol) was then addeddropwise. The reaction mixture was stirred overnight, diluted withdichloromethane, washed with 0.1 N hydrochloric acid, saturated aqueoussodium bicarbonate, and brine. The organic phase was dried overanhydrous magnesium sulfate, filtered, and evaporated to yield the crudetrichloroketone intermediate which without further purification, wasdissolved in acetone and treated with an excess of 1 N sodium hydroxide.The mixture was stirred overnight, and then diluted with isopropylacetate and acidified with 1 N hydrochloric acid. The organic layer waswashed with brine, dried over anhydrous magnesium sulfate, filtered, andevaporated to dryness. The solid residue was triturated with methanol toprovide the title compound (2.95 g) as a beige solid, m.p. 207-208° C.

[0598]¹H NMR (DMSO-d₆, 400 MHz) δ 3.49 (br, 3H), 6.12 (d, 1H), 6.72 (d,1H), 6.77 (s, 1H), 7.01 (d, 2H), 7.09 (m, 1H), 7.26 (m, 4H), 7.45 (m,2H), 7.61 (br, 1H), 12.35 (br, 1H).

[0599] MS [(+)APCI, m/z]: 491 [M+H]⁺.

[0600] Anal. Calcd for C₂₇H₂₀ClFN₂O₄: C 66.06, H 4.11, N 5.71. Found: C65.68, H 4.24, N 5.48.

[0601] Step D.N-(2,3-Dihydroxy-propyl)—N-(2,3,4-trihydroxy-butyl)-110-{[6-chloro-2′-fluoro-3-methoxy-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0602] The title compound was obtained in the manner of Example 1, StepF by coupling the[(6-chloro-3-methoxy-2′-fluoro-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid of Step C, with 4-(2,3-dihydroxy-propylamino)-butane-1,2,3-triol(1.25 equiv.) [prepared in the manner of Bennani et al., EP 0 558 395 B1(1993)].

EXAMPLE 31

[0603]N-Methyl-N-(2-hydroxy-1,1-bis-hydroxymethyl-ethyl)-{[10-(2-methoxy)-2′-methoxy-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-carboxamide

[0604]10-{[2-Methoxy-2′-chloro-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid (0.230 g, 0.54 mmol) [prepared from trifluoromethanesulfonic acid4-formyl-2-methoxy-phenyl ester of Example 21, Step A and 2-chlorophenylboronic acid, in the manner of Example 21, Steps B-E],1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.120 g,0.625 mmol) and 1-hydroxybenzotriazole (0.087 g, 0.625 mmol) were addedto a flask containing N,N-dimethylformamide (15 mL). To the homogeneoussolution was added 2-hydroxymethyl-2-methylamino-propane-1,3-diol[prepared in the manner of Bennani et al., EP 0 558 395 A1 (1993)](0.625 mmol) and stirring continued at room temperature overnight. Atthe end of this time the solution was poured into water and extractedwith ethyl acetate. The combined extracts were washed with water, driedand concentrated and the residue was chromatographed on silica gel usinga solvent system of 5% methanol in chloroform to provide the titleproduct

EXAMPLE 32

[0605]N-(2-Hydroxy-ethyl)—N-(2′,3′,4′-trihydroxy-butyl)-110-[(3,6-dimethoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0606] Step A.2,5-Dimethoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-carboxylic Acid

[0607] A suspension of 4-bromo-2,5-dimethoxybenzoic acid [prepared inthe manner of Bortnik et al., Zh. Org. Khim. 8, 340 (1972)] (2.43 g, 9mmol), 2-trifluoromethyl phenyl boronic acid (5.3 g, 28 mmol), andpotassium carbonate (6.21 g, 60 mmol) in dioxane (40 mL) was spargedwith nitrogen and treated with tetrakis(triphenylphosphine)palladium(0)(0.328 g, 0.2 mmol). The mixture was heated to reflux for 48 hours,cooled, acidified with 1 N hydrochloric acid and extracted with ethylacetate The extracts were dried over anhydrous magnesium sulfate,filtered and stripped to a solid which was used as such in the next step

[0608]¹H NMR (300 MHz, CDCl₃): δ 3.90 (s, 3H), 4.05 (s, 3H), 7.30 (d,1H), 7.70 (s, 1H).

[0609] Step B.10-{[3,6-Dimethoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine

[0610] The title compound was prepared in the manner of Example 33, StepA using 2,5-dimethoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-carboxylicacid of Step A (1.63 g, 5 mmol), oxalyl chloride (700 μL, 8 mmol),N,N-dimethylformamide (10 μL), 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.93 g, 5 mmol) and Hünig's base(1.78 ml, 10 mmol). Flash chromatography over silica gel using a solventgradient from 30% ethyl acetate in hexane to 100% ethyl acetate providedthe title compound (0.900 g) as a solid. Recrystallization fromacetone/hexane yielded white needles, m.p. 210-213° C.

[0611]¹H NMR (400 MHz, DMSO-d₆: 6 3.41 (s, 3H), 3.56 (s, 3H), 5.21 (br,4H), 5.90 (t, 1H), 5.96 (s, 1H), 6.50 (s, 1H), 6.80 (s, 1H), 7.00 (s,2H), 7.07 (s, 1H), 7.10 (t, 1H), 7.18 (d, 1H), 7.37 (d, 1H), 7.53 (t,1H), 7.62 (t, 1H), 7.73 (d, 1H).

[0612] MS [(+)ESI, m/z]: 493 [M+H]⁺.

[0613] Anal. Calcd. for C₂₈H₂₃F₃N₂O₃: C 68.29, H 4.71, N 5.69. Found: C67.98, H 4.66, N 5.61.

[0614] Step C.10-{[3,6-Dimethoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]-carbonyl}-10,11-dihydro-5H-pyrrolo[1,2-c][1,4]benzodiazepine-3-carboxylicAcid

[0615] Prepared from10-{[3,6-dimethoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]-carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepineof Step B and trichloroacetyl chloride, followed by basic hydrolysis ofthe intermediate trichloroacetate ester, in the manner of Example 1,Steps E and F.

[0616] Step D.N-(2-Hydroxy-ethyl)—N-(2′,3′,4′-trihydroxy-butyl)-10-[(3,6-dimethoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0617] The title compound was obtained in the manner of Example 2, bycoupling the10-[(3,6-dimethoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]-carbonyl}-10,11-dihydro-5H-pyrrolo[1,2-c][1,4]benzodiazepine-3-carboxylicacid of Step C and 4-[(2-hydroxy-ethylamino)-butane -1,2,3-triol (1equiv.) [prepared in the manner of Bennani et al., EP 0 558 395 A1(1993)].

EXAMPLE 33

[0618]N-(2,3-Dihydroxy-propyl)—N-(1-hydroxymethyl-2,3-dihydroxy-propyl)-10-{[3-methyl-4-(4-pyridinyl)phenyl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0619] Step A.(4-Bromo-3-methylphenyl)[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone

[0620] A solution of 4-bromo-3-methyl benzoic acid (4.3 g, 2 mmol) indry tetrahydrofuran (100 mL) was cooled to 0° C. under nitrogen. To thiswas added N,N-dimethylformamide (50 μL) followed by oxalyl chloride (2.2mL, 25 mmol) dropwise to control the gas evolution. When the gasevolution ceased, the mixture was warmed to reflux for 5 minutes thencooled to room temperature and concentrated in vacuo. The sample wastreated with tetrahydrofuran and evaporated to dryness (twice) to yieldthe crude acid chloride as an orange oil. A solution of10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (3.60 g, 20 mmol) andHünig's base (4.35 mL, 25 mmol) in dichloromethane was cooled to 0° C.,and a solution of the crude acid chloride in dichloromethane (25 mL) wasadded dropwise. The mixture was stirred overnight at room temperature,washed with 1 N hydrochloric acid, saturated aqueous sodium bicarbonateand brine. The solution was dried over anhydrous sodium sulfate,filtered and evaporated in vacuo to yield a solid (8.01 g) which waspurified by flash chromatography on silica gel eluting with 20% ethylacetate in hexane to provide the title compound (6.03 g) as a whitesolid.

[0621]¹H NMR (300 MHz, CDCl₃): δ 2.30 (s, 3H), 5.20 (br, 4H), 6.05 (d,2H), 6.70 (s, 1H), 6.85 (br, 2H), 7.17 (m, 2H), 7.30 (m, 2H), 7.37 (d,1H).

[0622] Step B.[3-Methyl-4-(pyridin-4-yl)phenyl]-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepin-10-yl]methanone

[0623] A suspension of(4-bromo-3-methylphenyl)-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanoneof Step A (1.14 g, 2.9 mmol), pyridine-4-boronic acid (0.368 mg, 2.9mmol) and sodium carbonate (0.760 g, 7.2 mmol) in a mixture of toluene(30 mL), water (10 mL), and ethanol (5 mL) was sparged with nitrogen for15 minutes. To this was added tetrakis(triphenylphosphine)palladium(0)(0.027 g) and the mixture was heated to reflux under a static pressureof nitrogen. After 24 hours additional boronic acid (0.128 mg, 1 mmol)and sodium carbonate (0.116 g) were added and the heating was continuedfor 24 hours. Additional catalyst (0.012 g) was added and heating wascontinued for another 24 hours. The mixture was partitioned betweenethyl acetate and hexane. The water layer was washed twice with ethylacetate and the combined organic layers were dried over anhydrousmagnesium sulfate and stripped to a solid. Flash chromatography of theresidue on silica gel eluting with 30% ethyl acetate in hexane provided0.379 g of the desired product which was recrystallized from ethylacetate/hexanes as tan plates, m.p. 208-210° C.

[0624]¹H NMR (400 MHz, DMSO-d₆): δ 1.75 (s, 3H), 1.77 (s, 3H), 5.18 (brs, 4H), 5.89 (s, 2H), 6.05 (brs, 1H), 6.08 (t, 1H), 6.69 (t, 1H), 6.85(brs, 1H), 7.03 (brs, 3H), 7.16 (t, 1H), 7.35 (d, 1H)

[0625] MS [(+)ESI, m/z]: 379 [M]⁺.

[0626] Anal. Calc'd for C₂₅H₂₁N₃O+0.5H₂O: C 77.30, H 5.71, N 10.82.Found: C 77.01, H 5.37, N 10.68

[0627] Step C.10-[3-Methyl-4-(4-pyridinyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicAcid

[0628] To a stirred solution of[3-methyl-4-(pyridin-4-yl)phenyl][10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanoneof Step B (5 mmol) and N,N-diisopropylethyl amine (12 mmol) indichloromethane (200 mL) cooled to 0° C. was added dropwise a solutionof trichloroacetyl chloride (12 mmol) in dichloromethane. Thetemperature was maintained at 0° C. until the addition was complete. Thereaction was stirred overnight as it warmed to room temperature. Thesolution was then washed with 10% aqueous sodium bicarbonate and theorganic layer was dried, concentrated and filtered through a pad ofsilica gel with 1:1 ethyl acetate/hexane containing 0.1% acetic acid.The filtrate was concentrated in vacuo and the residue was dissolved inacetone and 1N sodium hydroxide (2:1,v/v) and stirred at roomtemperature for 1 hour and then the pH was adjusted to pH 4 with glacialacetic acid. The solution was concentrated to one half the volume invacuo and the residue extracted with ethyl acetate. The combined organiclayers were dried and evaporated to an oil which was triturated withhexane to yield a solid (0.98 g).

[0629] Step D.N-(2,3-Dihydroxy-propyl)-N-(1-hydroxymethyl-2,3-dihydroxy-propyl)-10-{[3-methyl-4-(4-pyridinyl)phenyl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0630] The title compound was obtained in the manner of Example 1, StepG from the10-[3-methyl-4-(4-pyridinyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid of Step C and 3-(2,3-dihydroxy-propylamino)-butane-1,2-4-triol (1.2equiv.) [prepared in the manner of Bennani et al., EP 0 558 395 A1(1993)].

EXAMPLE 34

[0631]10-[(6-Phenyl-pyridin-3-yl)-carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid bis-(2-hydroxy-ethyl)-amide

[0632] Step A.10-(Methoxycarbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicAcid

[0633] A solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine(5 mmol) and N,N-diisopropylethyl amine (12 mmol) in dichloromethane(100 mL) was cooled to 0° C. and treated dropwise with trichloroacetylchloride (12 mmol) in dichloromethane (20 mL). The solution wasmaintained at 0° C. for two hours and then allowed to warm to roomtemperature overnight. The solution was then treated with methanol (25mL) and stirring was continued for 2 hours. The solution was washed with0.1 N hydrochloric acid, water and brine, dried over anhydrous magnesiumsulfate, filtered and concentrated to yield the title compound as awhite solid, m.p. 153-154° C. (dec.).

[0634] Anal. Calcd. for C₁₅H₁₄N₂O₄+0.06 C₄H₈O₂+0.07 C₃H₆O: C 62.77, H5.08, N 9.48. Found: C 62.26, H 5.22, N 9.37.

[0635] Step B.10-(Methoxycarbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicAcid bis-(2-hydroxy-ethyl)-amide

[0636] The title compound was prepared by coupling the10-(methoxycarbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid of step A with diethanolamine (1.2 equiv.), in the manner ofExample 1, Step G,

[0637] Step C.10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acidbis-(2-hydroxy-ethyl)-amide

[0638] A solution of10-(methoxycarbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid bis-(2-hydroxy-ethyl)-amide (5 mmol) of Step B in methanol (50 mL)was treated with potassium carbonate and stirred at room temperatureovernight. Water was then added to the solution and the pH adjusted to 6with 6N hydrochloric acid. The solution was saturated with solid sodiumchloride and extracted with dichloromethane. The combined organic layerswere dried over anhydrous magnesium sulfate and evaporated to dryness toyield the title compound.

[0639] Step D.10-[(6-Phenyl-pyridin-3-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid bis-(2-hydroxy-ethyl)-amide

[0640] A solution of 6-phenyl-nicotinyl chloride (6 mmol) [prepared bythe method of Ogawa (Ogawa et al WO 9534540)] in dichloromethane (20 mL)was added dropwise to a cold (0° C.) solution of10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acidbis-(2-hydroxy-ethyl)-amide of Step C (5 mmol) and N,N-diisopropylethylamine (6 mmol) in dichloromethane (100 mL). The solution was stirred at0° C. for 2 hours and then allowed to warm to room temperatureovernight. The solution was washed with pH 6 buffer, and brine, driedover anhydrous sodium sulfate, filtered and concentrated. The residuewas chromatographed on silica gel using 5% methanol in chloroformcontaining 0.5% ammonium hydroxide, to provide the title compound.

EXAMPLE 35

[0641] 10-{[6-(Naphthalen-1-yl)-pyridin-3-yl]-carbonyl}-N-methyl-N-[(2S,3R, 4R,5R)-2,3,4,5,6-pentahydroxy-hexyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0642] Step A.(6-Chloro-pyridin-3-yl)-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone

[0643] A solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine(100 mmol) and N,N′-diisopropylethyl amine (130 mmol) in dichloromethane(500 mL) was cooled to 0° C. 6-Chloronicotinoyl chloride (130 mmol) wasadded dropwise under nitrogen. The solution was stirred for one hour asit returned to room temperature. The reaction mixture was filteredthrough a sica gel pad, washed with 0.5 N sodium hydroxide and water,dried over anhydrous magnesium sulfate. The solution was again filteredthrough a silica gel pad and evaporated to dryness in vacuo. Theresidual oil crystallized from diethyl ether to provide the titlecompound as a colorless crystalline solid, m.p. 165-167° C.

[0644]¹H NMR (400 MHz, DMSO-d₆): δ 5.35 (br, 4H), 5.91 (t, 1H), 5.97 (s,1H), 6.83 (t, 1H), 7.0 (br d, 1H), 7.18 (t, 1H), 7.19 (t, 1H), 7.39 (d,1H), 7.46 (dd, 1H), 7.71 (d, 1H), 8.26 (s, 1H).

[0645] MS [El, m/z]: 323 [M]⁺.

[0646] Anal. Calcd. for C₁₈H₁₄ClN₃O: C 66.77, H 4.36, N 12.98. Found: C65.91, H 4.18, N 12.69.

[0647] Step B.[6-(Naphthalen-1-yl)-pyridin-3-yl]-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone

[0648] A suspension of(6-chloro-pyridin-3-yl)-[10,11-dihydro-5H-pyrrolo{2,1-c][1,4]benzodiazepin-10-yl]methanoneof Step A (0.645 g, 1.9 mmol) and naphthalene boronic acid (0.372 g, 2.1mmol) in a mixture of toluene (1.2 mL), ethanol (2 mL) and 1M aqueoussodium carbonate (0.4 mL) was sparged with nitrogen for 10 minutes. Tothis was added palladium(l) acetate (0.026 g, 0.1 mmol). The mixture washeated at reflux under a static pressure of nitrogen for 48 hrs. Thereaction was diluted with ethyl acetate and water. The organic layer waswashed with saturated aqueous sodium bicarbonate then water. The samplewas dried over anhydrous magnesium sulfate, filtered and concentrated invacuo to a brown oil. Flash chromatography of the residue on silica geleluting with 20-50% ethyl acetate in hexane, yielded 0.180 g of a solidwhich was recrystallized from chloroform to provide the title compoundas off white crystals, m.p. 155-158° C.

[0649]¹H NMR (400 MHz, DMSO-d₆): δ 5.40 (br, 4H), 5.93 (m, 1H), 5.99 (s,1H), 6.84 (s, 1H), 7.08 (brd, 1H), 7.16 (t, 1H), 7.23 (t, 1H), 7.52 (m,6H), 7.84 (d, 2H), 7.98 (dd, 2H), 8.55 (s, 1H).

[0650] MS [(+)ESI, m/z]: 416 [M+H]⁺.

[0651] Anal. Calcd. for C₂₈H₂₁N₃O+0.5H₂O: C 79.22, H 5.23, N 9.90.,Found: C 79.08, H 4.94, N 9.73.

[0652] Step C.10-{[6-(Naphthalen-1-yl)-pyridin-3-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[1,2-c][1.4]benzodiazepine-3-carboxylicAcid

[0653] Prepared from[6-(naphthalen-1-yl)-pyridin-3-yl][10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanoneof Step C by treatment with trichloroacetyl chloride, followed by basichydrolysis of the intermediate trichloroacetate ester in the manner ofExample 1, Step F.

[0654] Step D.10-{[6-(Naphthalen-1-yl)-pyridin-3-yl]-carbonyl}-N-methyl-N-[(2S, 3R,4R,5R)-2,3,4,5,6-pentahydroxy-hexyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0655] The title compound was prepared by the coupling of10-{[6-(naphthalen-1-yl)-pyridin-3-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[1,2-c][1.4]benzodiazepine-3-carboxylicacid of Step C, and N-methyl-D-glucamine (1.25 equiv) in the manner ofExample 4.

EXAMPLE 36

[0656]{(2S)-1-[(10-{[2-Methoxy-2(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)carbonyl]pyrrolidin-2-yl}-methanol

[0657] The title compound was prepared from10-{[2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid of Example 21, Step E (0.225 g, 0.48 mmol) and(S)-(+)-2-pyrrolidinemethanol (0.070 g, 0.7 mmol) in the manner ofExample 21, Step F, as an amorphous solid (0.112 g), m.p. 203-205° C.(dec).

[0658]¹H NMR (400 MHz, DMSO-d₆): δ 1.89-2.03 (m, 4H), 3.25 (s, 3H), 3.56(m, 2H), 4.35 (s, 2H), 5.43 (m, 2H), 5.56 (br, 2H), 6.06 (s, 1H), 6.41(s, 1H), 6.85-6.97 (m, 4H), 7.04 (t, 1H), 7.18 (t, 1H), 7.20 (d, 1H),7.23 (d, 1H), 7.42 (m, 2H), 7.56 (t, 1H), 7.62 (t, 1H ), 7.74 (d, 1H).

[0659] MS (El, m/z): 590 [M]⁺.

[0660] Anal. Calcd. for C₃₃H₃₀F₃N₃O₄: C 67.22, H 5.13, N 7.13. Found: C66.84, H 5.49, N 6.81

EXAMPLE 37

[0661]7,8-Dimethoxy-10-[(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid methyl-[(2S, 3R, 4R, 5R)-2,3,4,5,6-pentahydroxy-hexyl)-amide

[0662] Step A.7,8-Dimethoxy-(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine

[0663] The title compound was obtained as a white solid, m.p. 160-161°C., by reacting7,8-dimethoxy-(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(4-bromo-3-methyl-phenyl)-methanoneof Example 18, Step C with 2-methoxyphenyl boronic acid in the manner ofExample 18, Step D.

[0664]¹H NMR (400 MHz, DMSO-d₆): δ 1.95 (s, 3H), 3.45 (s, 3H), 3.65 (s,3H), 3.75 (s, 3H), 5.10 (br, 2H), 5.20 (s, 2H), 5.90 (t, 1H), 5.95 (s,1H), 6.60 (s, 1H), 6.75 (t 1H),.6.90 (s, 1H), 6.95-7.10 (m, 5H), 7.25(s, 1H), 7.35 (m, 1H).

[0665] MS [APCI, m/z]: 469 [M+H]⁺.

[0666] Anal. Calcd. for C₂₉H₂₈N₂O₄: C 74.34, H 6.02, N 5.98. Found: C74.01, H 6.10, N 5.94

[0667] Step B.7,8-Dimethoxy-10-[(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic Acidmethyl-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy-hexyl)-amide

[0668] Reaction of7,8-dimethoxy-(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepineof Step A with diphosgene and N-methyl-D-glucamine in the manner ofExample 18, Step E provided the title compound as a pale green solid,m.p. 110-120° C.

[0669]¹H NMR (400 MHz, DMSO-d₆): δ 1.95 (s, 3H), 3.05 (s, 3H), 3.30-3.60(m, 10H), 3.65 (s, 3H), 3.70 (s, 3H), 3.90 (s, 1H), 4.30 (t, 2H), 4.40(s, 1H), 4.50 (s, 1H), 4.90 (s, 1H), 5.10 (br, 2H), 5,25 (dd, 2H), 6.00(s, 1H), 6.30 (s, 1H), 6.50 (s, 1H), 6.90-7.10 (m, 6H), 7.25 (s, 1H),7.35 (s, 1H).

[0670] MS [APCI, m/z]: 690 [M+H]]⁺.

[0671] Anal. Calcd. for C₃₇H₄₃N₃O₁₀+0.5H₂O: C 63.60, H 6.35, N 6.01.Found: C 63.63, H 6.37, N 5.89.

EXAMPLE 38

[0672]9-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-9,10-dihydro-4H-3a,5,9-triaza-benzo[f]azulene-3-carboxylixAcid (3-hydroxy-propyl)-amide

[0673] Step A. 2-Chloromethyl-pyridine-3-carboxylic Acid Methyl Ester

[0674] A solution of methyl 2-methylnicotinate (20.0 g, 0.132 mol) andtrichloroisocyanuric acid (46.0 g, 0.198 mol) in dichloromethane (100mL) was stirred at room temperature overnight. The reaction mixture wasthen washed with saturated aqueous sodium carbonate and saturatedaqueous sodium chloride, dried over anhydrous magnesium sulfate,filtered, and the solvent evaporated in vacuo to provide the titlecompound as a yellow liquid (11.2 g), which is used as such in the nextstep.

[0675] Step B. 2-(2-Formyl-pyrrol-1-ylmethyl)-pyridine-3-carboxylic AcidMethyl Ester

[0676] To a suspension of sodium hydride (5.8 g, 0.12 mol) in dryN,N-dimethyl formamide (25 mL) was added slowly under nitrogen asolution of pyrrole 2-carboxaldehyde (10.5 g, 0.11 mol) inN,N-dimethylformamide (10 mL). The reaction mixture was stirred at roomtemperature for 30 minutes, then cooled to 5° C. and2-chloromethyl-pyridine-3-carboxylic acid methyl ester of Step A addedslowly while the temperature was being maintained at or below 20° C.After the addition was complete the reaction was stirred at roomtemperature for 30 minutes. The mixture was evaporated to dryness, andthe residue was dissolved in ethyl acetate (250 mL). This solution waswashed with water and dried over anhydrous magnesium sulfate. Thesolvent was then removed in vacuo leaving a dark crystalline solid (23.4g), which was purified by chromatography on silica gel eluting with agradient of ethyl acetate/petroleum ether to provide the title compoundas a tan crystalline solid (13.75 g), m.p. 91-93° C.

[0677] Step C.1-(3-Phenylacetyl-pyridin-2-ylmethyl)-1H-pyrrole-2-carbaldehyde

[0678] To a stirred solution of2-(2-formyl-pyrrol-1-ylmethyl)-pyridine-3-carboxylic acid methyl esterof Step B (13.65 g, 55.9 mmol) in methanol (50 mL) was added sodiumhydroxide (2.2 g, 55.9 mmol.). The reaction mixture was refluxed undernitrogen for 2 hours, and then the solvent was removed in vacuo. Aportion of the residual yellow solid.(5 g) was suspended in a mixture ofbenzyl alcohol (20 mL) and benzene (30 mL). Diphenylphosphoryl azide(6.54 g, 1.2 equiv.) was added, and the reaction was slowly heated toreflux. After refluxing for 1 hour, the mixture was cooled and washedwith water, dried over anhydrous magnesium sulfate, filtered andevaporated to dryness to provide the title compound as a tan crystallinesolid (4.4 g), m.p. 109-111° C.

[0679] Step D. 9,10-Dihydro-4H-3a,5,9-triaza-benzo[f]azulene

[0680] A stirred mixture of1-(3-phenylacetyl-pyridin-2-ylmethyl)-1H-pyrrole-2-carbaldehyde of StepC (1.0 g), in ethyl acetate (10 mL) containing 10% palladium on charcoal(10 mg.), magnesium sulfate (0.010 g) and 5 drops of acetic acid washydrogenated at atmospheric pressure until hydrogen uptake ceased. Thereaction mixture was then filtered through Celite and the solventremoved in vacuo. The crude product (yellow crystalline solid, 0.530 g)was purified by chromatography on silica gel eluting with a gradient ofethyl acetate in petroleum ether to provide the title product as ayellow crystalline solid, m.p. 171-172° C.

[0681] Step E.(4-Bromo-3-methyl-phenyl)-(4H,10H-3a,5,9-triaza-benzo[f]azulen-9-yl)-methanone

[0682] To a stirred solution of9,10-dihydro-4H-3a,5,9-triaza-benzo[f]azulene of Step D (1.0 g) indichloromethane (10 mL) was added 3-methyl-4-bromobenzoyl chloride (1.39g) and triethylamine (1.1 mL). After stirring for 2.5 hours, thereaction mixture was washed with water, dried over anhydrous magnesiumsulfate, filtered and the solvent removed in vacuo to provide the titleproduct as a tan crystalline solid (2.3 g), which was used withoutfurther purification.

[0683] Step F.(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)-(4H,10H-3a,5,9-triaza-benzo[f]azulen-9-yl)-methanone

[0684] A stirred mixture of (4-bromo-3-methyl-phenyl)-(4H,1OH-3a,5,9-triaza-benzo[f]azulen-9-yl)-methanone of Step E (1.0 g),2-trifluoromethylboronic acid (1.49 g, 3.0 equiv.), potassium phosphate(2.2 g) and a catalytic amount (0.050 g) of tetrakis(triphenylphosphine)palladium (0) in dioxane (10 mL) was refluxed for 2 hours. The solventwas then removed in vacuo and the residue dissolved in dichloromethane.The solution was then washed with water, dried over anhydrous magnesiumsulfate, filtered and evaporated to dryness. The residue was thenchromatographed on silica gel eluting with 5% ethyl acetate indichloromethane to yield a colorless gum which crystallized uponaddition of a little diethyl ether to provide the title compound as acream-colored crystalline solid (0.500 g), m.p. 153-155° C.

[0685]¹H NMR (DMSO-d₆, 400 MHz): δ 1.85 (s, 3H), 5.10 (s, 2H), 5.40 (s,2H), 5.90 (t, 1H), 6.00 (s, 1H), 6.90 (t, 1H), 6.94 (d, 1H), 7.03 (d,1H), 7.12 (dd, 1H), 7.23 (d, 1H), 7.28 (s, 1H), 7.37 (d, 1H), 7.58 (t,1H), 7.68 (t, 1H), 7.80 (d, 1H), 8.27 (d, 1H)

[0686] MS [(+)ESI, m/z]: 448 [M+H]⁺.

[0687] Anal. Calcd. for C₂₆H₂OF₃N₃O: C 69.79, H 4.51, N 9.39. Found: C69.91, H 4.30, N 9.26)

[0688] Step G.2,2,2-Trichloro-1-{[9-(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-9,10-dihydro-4H-3a,5,9-triaza-benzo[f]azulen-3-yl}-ethanone

[0689] To a solution of(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)-(4H,10H-3a,5,9-triaza-benzo[f]azulen-9-yl)-methanoneof Step F in dichloromethane was added trichloroacetyl chloride (1.1equiv.) and triethylamine (1.5 equiv,) After stirring overnight at roomtemperature, the reaction was washed with water, dried over anhydrousmagnesium sulfate, and evaporated to dryness to provide the crude titlecompound which was used as such in the next step.

[0690] Step H.9-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4yl)carbonyl]-9,10-dihydro-3a,5,9-triaza-benzo[f]azulen-3-carboxylicAcid

[0691] To a solution of2,2,2-trichloro-1-{[9-(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-9,10-dihydro-4H-3a,5,9-triaza-benzo[f]azulen-3-yl}-ethanoneof Step G in acetone was added 2.5 N sodium hydroxide (1.0 equiv.).After stirring overnight, the solvent was removed in vacuo leaving thecrude sodium salt of the carboxylic acid. This was dissolved inanhydrous ethanol and treated with 2 N hydrochloric acid (1.0 equiv.).The solvent was removed in vacuo, the residue redissolved in anhydrousethanol and the solvent again removed in vacuo. The crude title compoundwas then dried in vacuo over phosphorus pentoxide.

[0692] Step I.9-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-9,10-dihydro-4H-3a,5,9-triaza-benzo[f]azulene-3-carboxylicAcid (3-hydroxy-propyl)-amide

[0693] To a solution of the9-[(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4yl)carbonyl]-9,10-dihydro-3a,5,9-triaza-benzo[f]azulen-3-carboxylicacid (3.38 mmol) of Step H in N,N-dimethylformamide (20 mL) was added1-hydroxybenzotriazole (1.1 equiv.) and[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.2 equiv.), followed by 3-aminopropanol (1.2 equiv.) and N,N-diisopropylethylamine (1.5 equiv.). The reaction mixture was stirred overnight, thendiluted with ethyl acetate and washed with water and saturated aqueoussodium bicarbonate. The organic phase was dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. Purification of the residuewas effected by chromatography on silica gel eluting with a gradient ofmethanol in dichloromethane to provide the title compound as a whitefoam.

[0694] The following examples were prepared according to the generalprocedures described below.

[0695] General Procedure A

[0696] Step A. An appropriately substituted haloaryl carboxylic acid(1.1 mol) was converted to the acid chloride by using oxalyl chloride(1.5 mmol) and a catalytic amount of N,N-dimethylformamide indichloromethane. Upon consumption of the acid as determined by HPLCanalysis, all volatiles were removed in vacuo. The resulting residue wasdissolved in dichloromethane and added dropwise to a stirred and cooled(0° C.) solution of an appropriately substituted5H-pyrrolo[2,1-c][1,4]benzodiazepine (1 mmol) and N,N-diisopropylethylamine (1.2 mmol) in dichloromethane. After 1-16 hours, the mixture wasdiluted with dichloromethane and washed with 10% aqueous sodiumbicarbonate. The combined organic extracts were dried over anhydroussodium sulfate, filtered and concentrated.

[0697] Step B. To the residue was added an appropriately substitutedboronic acid (1.2 mmol), potassium carbonate (2.5 mmol),tetrabutylammonium bromide (1 mmol), palladium(II) acetate (3% mole) andwater/acetonitrile (1:1, 2 mL). The contents were heated to 70° C. for1.5 hours, then ethyl acetate was added and the organic phase washedwith water. The solution was filtered through a small plug of Celite andconcentrated to dryness.

[0698] Step C. The residue was dissolved in dichloromethane andN,N-diisopropylethyl amine (2 mmol) was added. The flask was purged withnitrogen and trichloroacetyl chloride was added dropwise to the stirredreaction mixture. After 16 hours, the reaction was quenched by addingaqueous potassium carbonate (100 g/300 mL) and the organic phaseremoved. The aqueous layer was extracted with additional dichloromethaneand the combined extracts dried over anhydrous sodium sulfate, filteredand concentrated .

[0699] Step D. The crude product from Step C was dissolved intetrahydrofuran (1 mL) and 2N sodium hydroxide (1.5 mL) was added. Themixture was heated (70° C.) for 1.5 hours, 2N hydrochloric acid wasadded and the product extracted with ethyl acetate. The organic phasewas dried, filtered and concentrated. The residue was purified by columnchromatography using a gradient of ethyl acetate in hexane contaning 1%glacial acetic acid as the eluant.

[0700] Step E. To a stirred solution of a carboxylic acid of Step Dabove (1.85 mmol) in anhydrous tetrahydrofuran (14 mL) was added1,1′-carbonyl diimidazole in one portion. The mixture was stirred atroom temperature (6-8 hours). The progress of the reaction was monitoredby HPLC and when the starting carboxylic acid was consumed, the mixturewas worked up to provide the intermediate imidazolide.

[0701] Step F. An aliquot of a tetrahydrofuran solution (400 μL, 0.05mmole) containing the imidazolide of Step E (0.05 mmol) was treated witha 0.25 M solution of an appropriate amine (0.1 mmol). The mixture washeated at 60° C. and the progress of the reaction followed by HPLC. Thesolvent was removed and the residue dissolved in dichloromethane (1 mL).The organic phase was washed with brine-water (1:1, v/v, 1 mL) and theaqueous layer extracted with additional dichloromethane. The combinedextracts were dried and evaporated to dryness and the residue waspurified by flash chromatography on silica gel. The column (prepacked in2.5% methanol in dichloromethane contaning 1% triethylamine) was elutedwith a solvent gradient from 2.5 to 5% methanol in dichloromethane, toprovide desired title compound. The desired title compounds were eitherobtained as crystalline solids by exposure to diethyl ether or werefurther converted into their salts by any of the following procedures.

[0702] Step G. Compounds prepared according to Step E that dissolved indiethyl ether were treated with a stoichiometric amount of 1 Nhydrochloric acid in diethyl ether whereby the hydrochloride saltsprecipitated out as white solids. Compounds that did not conform to theabove category, were dissolved in the minimal amount of tetrahydrofuran,then diluted with diethyl ether. The hydrochloride salts were formedupon addition of 1 N hydrochloric acid in diethyl ether with stirring.Compounds that did not immediately precipitate out of solution werestirred for 12-16 hours whereupon a white solid precipitated out.

[0703] General Procedure B

[0704] To a stirred solution of an appropriately substituted carboxylicacid of General Procedure A, Step D (2 mmol),1-ethyl-3-(3-dimethylamino-propyl) carbodiimide (0.229 g, 2.2 mmol) anda catalytic amount of 4-(dimethylamino)pyridine in dichloromethane (6mL) was added the appropriately substituted amine (2.2 mmol) indichloromethane (2 mL). The reaction was allowed to stir at roomtemperature for 16 hours, then diluted with dichloromethane. The organiclayer was washed with water, and saturated aqueous sodium bicarbonate,dried over anhydrous sodium sulfate and evaporated to dryness. Theresidue was purified by flash chromatography on silica gel (prepacked indichloromethane containing 2.5% methanol and 1% triethylamine and elutedwith a solvent gradient of 2.5 to 5% methanol in dichloromethane) toprovide the desired title compound.

[0705] General Procedure C

[0706] Triphosgene (742 mg, 2.5 mmol) was added to a stirred solution ofa carboxylic acid of General Procedure A, Step D (5.0 mmol) indichloromethane (10 mL). The clear solution was allowed to stir at roomtemperature (14 hours) after which time the solution turned red. To thereaction mixture was added a solution of the required amine (10.0 mmol)and N,N-diisopropylethyl amine (10.0 mmol) in dichloromethane (5 mL).The mixture was diluted with dichloromethane and washed with water andbrine. The organic phase was dried, filtered and concentrated to afforda residue which was purified by flash chromatography on silica gel. Thecolumn (prepacked in 2.5% methanol in dichloromethane contaning 1%triethylamine) was eluted with a solvent gradient from 2.5 to 5%methanol in dichloromethane, to provide the title compound.

[0707] General Procedure D

[0708] A stirred solution of a carboxylic acid of General Procedure A,Step D (3.54 mmol) and the appropriately substituted amine (3.72 mmol)in N,N-dimethylformamide (10 mL) was cooled to 0° C.N,N-diisopropylethyl amine (3.89 mmol) was added and the mixture stirredfor five minutes. O-(1-Benzotriazolyl)—N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HBTU) (1.42 g, 3.72 mmol) was added to the mixturein one portion. HPLC analysis revealed that the reaction was completewithin five minutes. The solvent was removed at reduced pressure. Theresidue was diluted with water and extracted with ethyl acetate. Thecombined extracts were dried and concentrated to dryness. The residuewas purified by flash chromatography on silica gel (prepacked in ethylacetate containing 2% triethylamine and eluted with 100% ethyl acetate)to provide the title compound.

[0709] General Procedure E

[0710] To a 0.25 M solution of a carboxylic acid of General Procedure A,Step D (200 μL) in N,N-dimethylformamide was added sequentially a 0.5 Msolution of N,N-diisopropylethyl amine (200 1L) inN,N-dimethylformamide, and a 0.25 M solution of0-(7-aza-1-benzotriazolyl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (210 μL) in N,N-dimethylformamide. Themixture was stirred vigorously at room temperature and then a 0.25 Msolution of the appropriately substituted amine (200 μL) inN,N-dimethylformamide was added. Stirring was continued for 24 hours atroom temperature, then the mixture was diluted-with ethyl acetate, andwashed with 1:1 water/brine. The organic layer was dried andconcentrated to dryness. The residue was purified by flashchromatography on silica gel (prepacked in ethyl acetate containing 2%triethylamine and eluted with 100% ethyl acetate) to provide the titlecompound.

[0711] General Procedure F

[0712] Step A. To a solution of an appropriately substituted anilinocarboxylic acid in methanol was added thionyl chloride. The mixture washeated for 16 hours. The volatiles were removed under reduced pressureand the hydrochloride salt of the carboxylic acid methyl ester wasrecovered after trituration with methanol/diethyl ether. The solid wasdissolved in concentrate hydrochloric acid and cooled. An aqueoussolution of sodium nitrite was added and the mixture was stirred at 0°C. for one hour. An aqueous solution of KI/I₂ was prepared and added tothe cooled mixture so that the reaction temperature did not exceed 0° C.After 1-2 hours the reaction was complete as evidenced by TLC/HPLCanalysis. The product was recovered by extraction with ethyl acetate.The combined extracts were dried, filtered and concentrated to affordthe desired substituted aryl iodide which could be further purified byrecrystallization.

[0713] Step B. To a solution of an appropriately substituted aryl halidemethyl ester of Step A (2 mmol) and an appropriately substituted boronicacid (2 mmol) in 20% aqueous acetone was added cesium carbonate (3 mmol)followed by palladium(II) acetate (60 μmol). The mixture was heated (70°C.) with stirring for 8-16 hours. The reaction was concentrated toremove the acetone after TLC/HPLC analysis indicated the reaction wascomplete. The aqueous phase was extracted with ethyl acetate and thecombined extracts were filtered through a pad of Celite. The filtratewas washed with 5% aqueous sodium bicarbonate and brine, dried overanhydrous sodium sulfate, filtered and evaporated to dryness. Theresidue was purified by flash chromatography on silica gel.

[0714] Step C. The product from Step B was dissolved in tetrahydrofuran(1 mL) and 2N sodium hydroxide (1.5 mL) was added. The mixture washeated (70° C.) for 1.5 hours, 2N hydrochloric acid was added and theproduct extracted with ethyl acetate. The organic phase was dried,filtered and concentrated. The residue was purified by columnchromatography using ethyl acetate in hexane contaning 1% glacial aceticacid as the eluant.

[0715] Step D. To a suspension of the carboxylic acid of Step C (60μmol) in dichloromethane (100 μL) was added a 0.45 M solution of oxalylchloride (200 μL) in dichloromethane followed by dichloromethane (100μL) containing a catalytic amount of N,N-dimethylformamide. The mixturewas allowed to sit at room temperature for 16 hours, then the volatileswere removed in vacuo to afford the crude acid chloride. A solution ofthe acid chloride in tetrahydrofuran (0.3 M, 200 μL) was utilized toacylate a solution (0.3 M, 200 μL) of an appropriately substituted5H-pyrrolo[2,1-c][1,4]benzodiazepine in tetrahydrofuran according to theGeneral Procedure A, Step A.

[0716] General Procedure G

[0717] A mixture of an appropriately substituted aryl bromide methylester (or an aryl iodode methyl ester of General Procedure F, Step A)(8.3 mmol), an appropriately substituted boronic acid (9.1 mmol),potassium carbonate (20.8 mmol), tetrabutylammonium bromide (or iodide)(8.3 mmol), palladium(II) acetate and water (8-9 mL) was stirred withheating (70° C.) for 1.5 hours, whereupon the reaction was deemedcomplete by HPLC analysis. The oily upper layer was extracted with ethylacetate, the extracts washed with brine, dried and concentrated todryness. The residue was filtered through a column of silica gel toprovide the desired coupled product of General Procedure F, Step B.

[0718] General Procedure H

[0719] The coupling of an appropriately substituted aryl bromide methylester (or an aryl iodide methyl ester of General Procedure F, Step A)(8.3 mmol) to an appropriately substituted pyridyl borane was carriedout using potassium hydroxide as the base, in the presence oftetrabutylammonium bromide (or iodide) and atetrakis(triphenylphoshine)palladium(0) catalyst essentially accordingto the published procedure of M. Ishikura, Synthesis, 936-938 (1994), toprovide the desired coupled product of General Procedure F, Step B.

[0720] General Procedure I

[0721] The coupling of an appropriately substituted aryl bromide methylester (or an iodide methyl ester of General Procedure F, Step A) (8.3mmol) to an appropriately substituted boronic acid was carried outessentially according to General Procedure F, Step B except that thesolvent was acetonitrile.

[0722] General Procedure J

[0723] The desired substituted aryl iodide of General Procedure F, StepA was prepared by reaction of an appropriately substituted aminocarboxylic acid in concentrated hydrochloric acid at 0° C. with anaqueous solution of sodium nitrite followed by the addition of anaqueous solution of potassium/iodine at 0° C., followed byesterification of the resulting iodo aryl carboxylic acid withmethanolic hydrochloric acid.

[0724] General Procedure K

[0725] The acylation of an activated appropriately substitutedarylpyridine carboxylic acid of Procedure H was carried out bydissolving the acid (0.06 mmol) in a solution of oxalyl chloride indichloromethane (12 mg/200 μL) followed by a catalytic amount ofN,N-dimethylformamide in dichloromethane (100 μL). After stirring atroom temperature for 16 hours, the volatiles were removed andtetrahydrofuran added, followed by the addition of a solution of theappropriately substituted 5H-pyrrolo[2,1-c][1,4]benzodiazepine andN,N-diisopropylethyl amine (1:2 molar ratio) in tetrahydrofuran. Afterstirring for 20 hours, the reaction was worked up essentially asdescribed in General Procedure A, Step A.

EXAMPLE 39

[0726]{10-[(6-Chloro-3-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-hydroxyethyl)-1-piperazinyl]methanone

[0727] HRMS [(+)ESI, m/z]: 599.24233 [M+H]⁺. Calcd. for C₃₄H₃₆ClN₄O₄:599.24196

EXAMPLE 40

[0728][4-(2-Hydroxyethyl)-1-piperazinyl]{10-[(2′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0729] HRMS [(+)ESI, m/z]: 565.28069 [M+H]⁺. Calcd. for C₃₄H₃₇N₄O₄.565.28094

EXAMPLE 41

[0730][4-(2-Hydroxyethyl)-1-piperazinyl]{10-[3-methoxy-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0731] HRMS [(+)ESI, m/z]: 601.27922 [M+H]⁺. Calcd. for C₃₇H₃₇N₄O₄601.28094

EXAMPLE 42

[0732][4-(2-Hydroxyethyl)-1-piperazinyl]{10-[(2-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0733] HRMS [(+)ESI, m/z]: 565.28120 [M+H]⁺. Calcd. for C₃₄H₃₇N₄O₄565.28094

EXAMPLE 43

[0734]{10-[(2,2′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-hydroxyethyl)-1-piperazinyl]methanone

[0735] HRMS [(+)ESI, m/z]: 581.27378 [M+H]⁺. Calcd. for C₃₄H₃₇N₄O₅581.27585

EXAMPLE 44

[0736][4-(2-Hydroxyethyl)-1-piperazinyl]{10-[(3′-methoxy-2-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0737] HRMS [(+)ESI, m/z]: 565.27969 [M+H]⁺. Calcd. for C₃₄H₃₇N₄O₄565.28094

EXAMPLE 45

[0738][4-(2-Hydroxyethyl)-1-piperazinyl]{10-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0739] HRMS [(+)ESI, m/z]: 535.26943 [M+H]⁺. Calcd. for C₃₃H₃₅N₄O₃535.27037

EXAMPLE 46

[0740]{10-[(2,2′-Dimethyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-hydroxyethyl)-1-piperazinyl]methanone

[0741] HRMS [(+)ESI, m/z]: 549.28658 [M+H]⁺. Calcd. for C₃₄H₃₇N₄O₃:549.28602

EXAMPLE 47

[0742][4-(2-Hydroxyethyl)-1-piperazinyl]{10-[(2′-methoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone

[0743] HRMS [(+)ESI, m/z]: 551.26476 [M+H]⁺. Calcd. for C₃₃H₃₅N₄O₄551.26529

EXAMPLE 48

[0744][4-(2-Hydroxyethyl)-1-piperazinyl](10-{[2-methyl-2′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)methanone

[0745] HRMS [(+)ESI, m/z]: 603.25707 [M+H]⁺. Calcd. for C₃₄H₃₄F₃N₄O₃603.2577

EXAMPLE 49

[0746]{10-[(6-Chloro-3,3′-dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-hydroxyethyl)-1-piperazinyl]methanone

[0747] HRMS [(+)ESI, m/z]: 615.23646 [M+H]⁺. Calcd. for C₃₄H₃₆ClN₄O₅615.23688

EXAMPLE 50

[0748]{10-[(2,3′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-hydroxyethyl)-1-piperazinyl]methanone

[0749] HRMS [(+)ESI, m/z]: 581.27577 [M+H]⁺. Calcd. for C₃₄H₃₇N₄O₅581.27585

EXAMPLE 51

[0750]10-(3-Methoxy-4-pyridin-3-yl-benzoyl)-10,11-dihydro-5H-pyrrolo[1,2-c][1,4]benzodiazepin-3-carboxylicAcid (2,3-dihydroxy-propyl)-methyl-amide

[0751] MS [(+)ESI, m/z]: 527 [M+H]⁺. Calcd. for C₃₀H₃₁N₄O₅ 527.23.

[0752] General Procedure L

[0753] Step A. To a stirred cooled (0° C.) solution of an appropriatelysubstituted10-(4-amino)benzoyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine(10 mmol) in dichloromethane (20 mL) was added N,N-diisopropylethylamine (2.09 mL, 12 mmol) followed by the addition of9-fluorenylmethylchloroformate (2.85 g, 11 mmol) in one portion. Thereaction was allowed to warm to room temperature. TLC analysis was usedto monitor the progress of the reaction and after 8 hours, indicatedthat a single product was formed. The reaction mixture was diluted withdichloromethane and washed with water and brine. The organic phase wasdried over anhydrous sodium sulfate, filtered and concentrated. Theresulting residue was purified by flash column chromatography (BiotageFlash 40S, 10-20% EtOAc-hexanes) to provide the desired appropriatelysubstituted4-(fluorenylmethoxycarbonyl)-10,1-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine.

[0754] Step B. Trichloroacetyl chloride (3.35 mL, 30 mmol) was added toa solution of an appropriately substituted4-(fluorenylmethoxycarbonyl)-10,1-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepineof Step A (10 mmol) and N,N-didisopropylethyl amine (3.48 mL, 20 mmol)in dichloromethane, and the solution was stirred at ambient temperaturefor 2 hours. An aqueous solution of sodium bicarbonate (0.5 M) was addedto the mixture and the organic layer was separated, dried over anhydroussodium sulfate, filtered and concentrated. The residue was dissolved ina solution of piperidine in N,N-dimethylformamide (20%, v/v) and stirreduntil the starting material was no longer observed by HPLC/TLC analysis.The mixture was diluted with ethyl acetate and washed with water. Theorganic phase was dried over anhydrous sodium sulfate, filtered andconcentrated. The desired appropriately substituted2,2,2-trichloro-1-[10-(4-aminobenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}-ethanonewas isolated by flash chromatography (Biotage, Flash 40M, gradientelution Of 20-30% ethyl acetate in hexanes).

[0755] Step C. An appropriately substituted 1,4-diketone (25 mmol) wasadded to a vial containing an appropriately substituted aniline of StepB (4.4 mmol) followed by the addition of acetic acid (1 mL). Thecontents of the vial were stirred and heated (80° C.) without the vialcapped (to allow for the removal of water). After 1 hour the solutionwas diluted with ethyl acetate (20 mL). The organic phase was washedwith water, aqueous sodium bicarbonate and brine. The organic layer wasdried over anhydrous sodium sulfate, filtered and concentrated. Theresulting residue was purified by flash column chromatography to affordthe desired appropriately substituted2,2,2-trichloro-1-{10-{4-(1H-pyrrol-1-yl)-benzoyl]-10,11-dihydro[2,1-c][1,4]benzodiazepin-3-yl}-ethanone.

[0756] Step D. The material from Step C (3.85 mmol) was dissolved intetrahydrofuran (10 mL) and treated with aqueous sodium hydroxide (2 N,3 mL). The mixture was allowed to stir with heating (80° C.) overnight.After cooling to room temperature, aqueous hydrochloric acid (2 N, 3.2mL) was added and product was recovered by extraction with ethylacetate. The combined extracts were evaporated and the residue purifiedby flash column chromatography, eluting with a gradient of 20 to 50%ethyl acetate in hexanes to provide the desired appropriatelysubstituted title compound.

EXAMPLE 52

[0757]{10-[4-(2,5-Dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-hydroxyethyl)-1-piperazinyl]methanone

[0758] HRMS [(+)ESI, m/z]: 568.29191 [M+H]⁺. Calcd. for C₃₃H₃₈N₅O₄568.29184

What is claimed:
 1. A compound of the formula:

wherein:

is selected from the moieties:

R₁ and R₂ are, independently, selected from hydrogen, (C₁-C₆) loweralkyl, halogen, cyano, trifluoromethyl, hydroxy, amino, (C₁-C₆) loweralkylamino, (C₁-C₆) lower alkoxy, —OCF₃, (C₁-C₆) lower alkoxycarbonyl,—NHCO[(C₁-C₆)lower alkyl], carboxy, —CONH₂, —CONH[(C₁-C₆) lower alkyl]or —CON-[(C₁-C₆) lower alkyl]₂; R₃ is a substituent selected fromhydrogen, (C₁-C₆) lower alkyl, (C₁-C₆) lower alkoxy, hydroxy, amino,(C₁-C₆) lower alkylamino, —CO lower alkyl (C₀-C₆), or halogen; R₄consists of the moiety B-C; wherein: B is selected from the groupconsisting of:

and C is selected from the group consisting of:

wherein: A is CH or N; R₅, R₆, R₇, R₈, R₉, R₁₀ are, independently,selected from hydrogen, (C₁-C₆) lower alkyl, (C₁-C₆) lower alkoxy,hydroxy (C₁-C₆) lower alkyl, alkoxy, (C₁-C₆) lower alkyl, acyloxy,(C₁-C₆) lower alkyl, (C₁-C₆) lower alkylcarbonyl, (C₃-C₆) lower alkenyl,(C₃-C₆) lower alkynyl, (C₃-C₈) cycloalkyl, formyl, cycloalkylcarbonyl,carboxy, lower alkoxycarbonyl, cycloalkyloxycarbonyl, arylalkyloxycarbonyl, carbamoyl, —O—CH₂—CH═CH₂, halogen, halo lower alkyl,trifluoromethyl, —OCF₃, —S[(C₁-C₆) lower alkyl], —OC(O)N-[(C₁-C₆) loweralkyl]₂, —CONH[(C₁-C₆) lower alkyl], —CON-[(C₁-C₆) lower alkyl]₂,(C₁-C₆) lower alkylamino, di-[(C₁-C₆) lower alkyl]amino, (C₁-C₆) loweralkyl di-[(C₁-C₆) lower alkyl]amino, hydroxy, cyano,trifluoromethylthio,nitro, amino, (C₁-C₆) lower alkylsulfonyl, aminosulfonyl, (C₁-C₆) loweralkylaminosulfonyl,

phenyl or naphthyl; R₁₁ and R₁₂ are, independently, selected from thegroup ofhydrogen, (C₁-C₆) lower alkyl, (C₃-C₆) lower alkenyl, (C₁-C₆)lower alkynyl, cyclo lower alkyl, or aryl, optionally substituted byhydroxy, (C₁-C₆) lower alkyl, (C₁-C₆) lower alkoxy, halogen, cyano,—SO₂[(C₁-C₆) lower alkyl], or —S[(C₁-C₆) lower alkyl]; R is selected,independently, from any of the following groups:

R₁₃ is selected from hydrogen, (C₁-C₆) lower alkyl, (C₇-C₁₂) aryl loweralkyl wherein the aryl moiety is optionally substituted with loweralkoxy, or any of the following groups:

R₁₄ is selected from any of the following groups:

R₁₅ and R₁₆ are, independently, chosen from the group ofhydrogen,(C₁-C₆) lower alkyl or (C₇-C₁₂) aryl lower alkyl; R₁₇ is hydrogen, or(C₁-C₆) lower alkyl; R₁₈ is hydroxy, lower alkoxy, or OP wherein P is ahydroxy protecting group; R₁₉ is selected from the group of hydrogen,(C₁-C₆) lower alkyl or (C₇-C₁₂) aryl lower alkyl; R₂₀ is selected fromthe group of-N-[lower alkyl]₂, or —N-[aryl lower alkyl]₂;

R₂₁ is hydrogen, (C₁-C₆) lower alkyl, or R₂₉; R₂₂ is selected from thegroup of (C₁-C₆) lower alkyl, —COR₁₈, —CONH[lower alkyl], —CON-[loweralkyl]₂; R₂₃ is aryl, optionally substituted by one to threesubstituents chosen from hydroxy, (C₁-C₆) lower alkoxy, aryloxy loweralkyl, or halogen; R₂₄ represents one to four substituents chosen,independently, from the group of hydrogen or (C₁-C₆) lower alkyl; R₂₅ isselected the group of

R₂₆ is (C₁-C₆) lower alkyl, or aryl (C₁-C₆) lower alkyl; R₂₇ and R₂₈taken together represent one to four substituents chosen, independently,from the group of R₁₈, R₂₉, (C₁-C₆) lower alkyl , [(C₁-C₆) loweralkyl]₂, —CONH[lower alkyl], —CON-[lower alkyl]₂, R₃₂, or

 with the proviso that at least one substituent is not (C₁-C₆) loweralkyl, -[(C₁-C₆) lower alkyl]₂, —CONH[lower alkyl] or —CON-[loweralkyl]₂; and with further proviso that R₂₇ and R₂₈ can be joinedtogether to form a 5 or 6 membered saturated ring optionally substitutedby one or more substituents selected from R₁₈ or R₂₉; R₂₉ is selectedfrom the group of hydroxy lower alkyl, lower alkoxy lower alkyl, orlower alkyl OP wherein P is a hydroxy protecting group; R₃₀ is (C₁-C₆)lower alkyl, or (C₇-C₁₂) aryl lower alkyl; R₃₁ represents one to foursubstituents chosen from the group of R₁₈ or R₂₉;

R₃₃ is hydrogen or (C₁-C₆) lower alkyl; X and Y are either CH, or N; pis an integer from 0 to 1; q is an integer from 2 to 4; r is an integerfrom 0 to 3; s in integer from 0 to 2 t is an integer from 1 to 2; andthe pharmaceutically acceptable salts, or pro-drug forms thereof.
 2. Acompound of claim 1 having the formula:

wherein R, R₁, R₂, R₃, R₅, R₆, R₇, R₈, R₉, R₁₀ are as defined in claim1, or a pharmaceutically acceptable salt form thereof.
 3. A compound ofclaim 1 of the formula:

wherein:

is selected from the moieties:

R₁ and R₂ are, independently, selected from hydrogen, (C₁-C₆)loweralkyl, halogen, cyano, trifluoromethyl, hydroxy, amino, (C₁-C₆) loweralkylamino, (C₁-C₆) lower alkoxy, —OCF₃, (C₁-C₆) lower alkoxycarbonyl,—NHCO[(C₁-C₆)lower alkyl], carboxy, —CONH₂, —CONH[(C₁-C₆) lower alkyl]or —CON-[(C₁-C₆) lower alkyl]₂; R₃ is a substituent selected fromhydrogen, (C₁-C₆) lower alkyl, (C₁-C₆) lower alkoxy, hydroxy, amino,(C₁-C₆) lower alkylamino, —CO lower alkyl (C₁-C₆), or halogen; R₄consists of the moiety B-C; wherein: B is selected from the groupconsisting of:

and C is selected from the group consisting of:

wherein: A is CH or N; R₅, R₆, R₇, R₈, R₉, R₁₀ are, independently,selected from hydrogen, (C₁-C₆) lower alkyl, (C₁-C₆) lower alkoxy,hydroxy (C₁-C₆) lower alkyl, alkoxy (C₁-C₆) lower alkyl, acyloxy (C₁-C₆)lower alkyl, (C₁-C₆) lower alkylcarbonyl, (C₃-C₆) lower alkenyl, (C₃-C₆)lower alkynyl, (C₃-C₈) cycloalkyl, formyl, cycloalkylcarbonyl, carboxy,lower alkoxycarbonyl, cycloalkyloxycarbonyl, aryl alkyloxycarbonyl,carbamoyl, —O—CH₂—CH═CH₂, halogen, halo lower alkyl, trifluoromethyl,—OCF₃, —S[(C₁-C₆) lower alkyl], —OC(O)N-[(C₁-C₆) lower alkyl]₂,—CONH[(C₁-C₆) lower alkyl], —CON-[(C₁-C₆) lower alkyl]₂, (C₁-C₆) loweralkylamino, di-[(C₁-C₆) lower alkyl]amino, (C₁-C₆) lower alkyldi-[(C₁-C₆) lower alkyl]amino, hydroxy, cyano, trifluoromethylthio,nitro, amino, (C₁-C₆) lower alkylsulfonyl, aminosulfonyl, (C₁-C₆) loweralkylaminosulfonyl,

phenyl or naphthyl; R₁₁ and R₁₂ are, independently, selected from thegroup of hydrogen, (C₁-C₆) lower alkyl, (C₃-C₆) lower alkenyl, (C₁-C₆)lower alkynyl, cyclo lower alkyl, or aryl, optionally substituted byhydroxy, (C₁-C₆) lower alkyl, (C₁-C₆) lower alkoxy, halogen, cyano,—SO₂[(C₁-C₆) lower alkyl], or —S[(C₁-C₆) lower alkyl]; R is selected,independently, from the groups:

R₁₃ is selected from hydrogen, (C₁-C₆) lower alkyl, (C₇-C₁₂) aryl loweralkyl wherein the aryl moiety is optionally substituted with loweralkoxy, or any of the following groups:

R₁₄ is selected from the groups:

R₁₅ and R₁₆ are, independently, chosen from the group of hydrogen,(C₁-C₆) lower alkyl or (C₇-C₁₂) aryl lower alkyl; R₁₈ is hydroxy, loweralkoxy, or OP wherein P is a hydroxy protecting group; R₁₉ is selectedfrom the group of hydrogen, (C₁-C₆) lower alkyl or (C₇-C₁₂) aryl loweralkyl; R₂₁ is hydrogen, (C₁-C₆) lower alkyl, or R₂₉; R₂₅ is selectedfrom the groups:

R₂₆ is (C₁-C₆) lower alkyl, or aryl (C₁-C₆) lower alkyl; R₂₉ is selectedfrom the group of hydroxy lower alkyl, lower alkoxy lower alkyl, orlower alkyl OP wherein P is a hydroxy protecting group; p is an integerfrom 0 to 1; q is an integer from 2 to 4; t is an integer from 1 to 2;or a pharmaceutically acceptable salt thereof.
 4. A compound of claim 1of the formula:

R₁ and R₂ are, independently, selected from hydrogen, (C₁-C₆)loweralkyl, halogen, cyano, trifluoromethyl, hydroxy, amino, (C₁-C₆) loweralkylamino, (C₁-C₆) lower alkoxy, —OCF₃, (C₁-C₆) lower alkoxycarbonyl,—NHCO[(C₁-C₆)lower alkyl], carboxy, —CONH₂, —CONH[(C₁-C₆) lower alkyl]or —CON-[(C₁-C₆) lower alkyl]₂; R₃ is a substituent selected fromhydrogen, (C₀-C₆) lower alkyl, (C₁-C₆) lower alkoxy, hydroxy, amino,(C₁-C₆) lower alkylamino, —CO lower alkyl (C₁-C₆), or halogen; R₄consists of the moiety B-C; wherein: B is selected from the groupconsisting of:

and C is selected from the group consisting of:

wherein: A is CH or N; R₅, R₆, R₇, R₈, R₉, R₁₀ are, independently,selected from hydrogen, (C₁-C₆) lower alkyl, (C₁-C₆) lower alkoxy,hydroxy(C₁-C₆) lower alkyl, alkoxy(C₁-C₆) lower alkyl, acyloxy(C₁-C₆)lower alkyl, (C₀-C₆) lower alkylcarbonyl, (C₃-C₆) lower alkenyl, (C₃-C₆)lower alkynyl, (C₃-C₈) cycloalkyl, formyl, cycloalkylcarbonyl, carboxy,lower alkoxycarbonyl, cycloalkyloxycarbonyl, aryl alkyloxycarbonyl,carbamoyl, —O—CH₂—CH═CH₂, halogen, halo lower alkyl, trifluoromethyl,—OCF₃, —S[(C₁-C₆) lower alkyl], —OC(O)N-[(C₁-C₆) lower alkyl]₂,—CONH[(C₁-C₆) lower alkyl], —CON-[(C₁-C₆) lower alkyl]₂, (C₁-C₆) loweralkylamino, di-[(C₁-C₆) lower alkyl]amino, (C₀-C₆) lower alkyldi-[(C₁-C₆) lower alkyl]amino, hydroxy, cyano,trifluoromethylthio,nitro, amino, (C₁-C6) lower alkylsulfonyl, aminosulfonyl, (C₀-C₆) loweralkylaminosulfonyl,

phenyl or naphthyl; R₁₁ and R₁₂ are, independently, selected from thegroup ofhydrogen, (C₀-C₆) lower alkyl, (C₃-C₆) lower alkenyl, (C₀-C₆)lower alkynyl, cyclo lower alkyl, or aryl, optionally substituted byhydroxy, (C₀-C₆) lower alkyl, (C₀-C₆) lower alkoxy, halogen, cyano,—SO₂[(C₁-C₆) lower alkyl], or —S[(C₁-C₆) lower alkyl]; R is selected,independently, from the groups:

R₁₃ is selected from hydrogen, (C₁-C₆) lower alkyl, (C₇-C₁₂) aryl loweralkyl wherein the aryl moiety is optionally substituted with loweralkoxy, or any of the following groups:

R₁₄ is selected from the groups:

R₁₅ and R₁₆ are, independently, chosen from the group of hydrogen,(C₁-C₆) lower alkyl or (C₇-C₁₂) aryl lower alkyl; R₁₈ is hydroxy, loweralkoxy, or OP wherein P is a hydroxy protecting group; R₁₉ is selectedfrom the group of hydrogen, (C₁-C₆) lower alkyl or (C₇-C₁₂) aryl loweralkyl; R₂₁ is hydrogen, (C₁-C₆) lower alkyl, or R₂₉; R₂₅ is selectedfrom the groups:

R₂₆ is (C₁-C₆) lower alkyl, or aryl (C₁-C₆) lower alkyl; R₂₉ is selectedfrom the group of hydroxy lower alkyl, lower alkoxy lower alkyl, orlower alkyl OP wherein P is a hydroxy protecting group; p is an integerfrom 0 to 1; q is an integer from 2 to 4; t is an integer from 1 to 2;or a pharmaceutically acceptable salt or pro-drug form thereof.
 5. Acompound of claim 1 selected from the group of:10-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid bis-(2-hydroxy-ethyl)-amide;10-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid (2,3-dihydroxy-propyl)-methyl-amide;10-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid(2-hydroxy-1,1-bis-hydroxymethyl-ethyl)-amide;10-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid methyl-((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy-hexyl)-amide;(2S)-3-{4-[(10-{[2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)carbonyl]piperazin-1-yl}propane-1,2-diol;(2R)-3-{4-[(10-{[2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)carbonyl]piperazin-1-yl}propane-1,2-diol;Methyl2-{4-[(10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)carbonyl]piperazin-1-yl}ethylether;(2R)-1-Methoxy-3-{4-[(10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)carbonyl]piperazin-1-yl}propan-2-ol;[3-({4-[(2S)-2-Hydroxy-3-methoxypropyl]-1-piperazinyl}carbonyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl][2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]methanone;orN-(2,3-Dimethoxypropyl)-N-methyl-10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;or a pharmaceutically acceptable salt form thereof.
 6. A compound ofclaim 1 selected from the group of:10-[(2-Methyl-2′-trifluoromethyl-[11′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acidmethyl-[(2-oxo-[1,3]dioxolan-4-yl)methyl]-amide;N-[((4S,5S)-5-{(R)-Hydroxy[(4R)-2-oxo-1,3-dioxolan-4-yl]methyl}-2-oxo-1,3-dioxolan-4-yl)methyl]-N-methyl-10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c]benzodiazepine-3-carboxamide;2-(Acetyloxy)-1-({methyl[(10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)carbonyl]amino}methyl)ethylacetate;10-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid (2,3-dihydroxy-propyl)-methyl-amide;N-[(2S)-2,3-Dihydroxypropyl]-10-[(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[(2R)-2,3-Dihydroxypropyl]-10-[(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(2′-Methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid methyl-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)-amide;N-(2,3-Dihydroxypropyl)-7,8-dimethoxy-N-methyl-10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N,N-Bis(2-hydroxyethyl)-7,8-dimethoxy-10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;or10-{[6-Chloro-3-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-methyl-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy-hexyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;or a pharmaceutically acceptable salt form thereof.
 7. A compound ofclaim 1 selected from the group of:N-(2,3-Dihydroxypropyl)-10-{[2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-[(3-Dimethylamino)-2-hydroxy-propyl]-10-{[2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-{[2-Methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-N-methyl-N-[(2R,3S,4R,5S)-2,3,4,5,6-pentahydroxy-hexyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[4-(Naphthalen-1-yl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid bis-(2-hydroxy-ethyl)-amide;2-{4-[110-{[2-Chloro-4-(naphthalen-1-yl)phenyl]carbonyl}-(10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)carbonyl]piperazine-1-yl}-1-hydroxyethane;10-{[4-(4-Methyl-naphthalen-1-yl)phenyl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid (2,3-dihydroxy-propyl)—N-methylamide;10-[(3-Methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid methyl-[(2S, 3R, 4R, 5R)-2,3,4,5,6-pentahydroxy-hexyl]-amide;{10-[(2′-Chloro-6-chloro-3-methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-yl}[(2S,5S)-bis-hydroxymethyl-(3R, 4R)-bis-hydroxy-pyrrolidin-1-yl]-methanone;10-[(6-Chloro-2′-ethoxy-3-methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-N-methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid methyl-(2,3,4-trihydroxybutyl)-amide; orN-(2,3-Dihydroxy-propyl)-N-(2,3,4-trihydroxy-butyl)-10-{[6-chloro-2′-fluoro-3-methoxy-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;or a pharmaceutically acceptable salt form thereof.
 8. A compound ofclaim 1 selected from the group of:N-Methyl-N-(2-hydroxy-1,1-bis-hydroxymethyl-ethyl)-{[10-(2-methoxy)-2′-methoxy-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-carboxamide;N-(2-Hydroxy-ethyl)—N-(2′,3′,4′-trihydroxy-butyl)-10-[(3,6-dimethoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;N-(2,3-Dihydroxy-propyl)—N-(1-hydroxymethyl-2,3-dihydroxy-propyl)-10-{[3-methyl-4-(4-pyridinyl)phenyl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;10-[(6-Phenyl-pyridin-3-yl)-carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid bis-(2-hydroxy-ethyl)-amide;10-{[6-(Naphthalen-1-yl)-pyridin-3-yl]-carbonyl}-N-methyl-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy-hexyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide;{(2S)-1-[(10-{[2-Methoxy-2′(trifluoromethyl)[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)carbonyl]pyrrolidin-2-yl}-methanol;7,8-Dimethoxy-10-[(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylicacid methyl-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy-hexyl)-amide;9-[(2-Methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-9,10-dihydro-4H-3a,5,9-triaza-benzo[f]azulene-3-carboxylixacid (3-hydroxy-propyl)amide;{10-[(6-Chloro-3-methoxy-2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-hydroxyethyl)-1-piperazinyl]methanone;or[4-(2-Hydroxyethyl)-1-piperazinyl]{10-[(2′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;or a pharmaceutically acceptable salt form thereof.
 9. A compound ofclaim 1 selected from the group of:[4-(2-Hydroxyethyl)-1-piperazinyl]{10-[3-methoxy-4-(1-naphthyl)benzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;[4-(2-Hydroxyethyl)-1-piperazinyl]{110-[(2-methoxy-2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;{10-[(2,2′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-hydroxyethyl)-1-piperazinyl]methanone;[4-(2-Hydroxyethyl)-1-piperazinyl]{10-[(3′-methoxy-2-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;[4-(2-Hydroxyethyl)-1-piperazinyl]{10-[(2′-methyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;{10-[(2,2′-Dimethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-hydroxyethyl)-1-piperazinyl]methanone;[4-(2-Hydroxyethyl)-1-piperazinyl]{10-[(2′-methoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}methanone;[4-(2-Hydroxyethyl)-1-piperazinyl](10-{[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl)methanone;{10-[(6-Chloro-3,3′-dimethoxy-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-hydroxyethyl)-1-piperazinyl]methanone;{10-[(2,3′-Dimethoxy[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-hydroxyethyl)-1-piperazinyl]methanone;10-(3-Methoxy-4-pyridin-3-yl-benzoyl)-10,11-dihydro-5H-pyrrolo[1,2-c][1,4]benzodiazepin-3-carboxylicacid (2,3-dihydroxy-propyl)-methyl-amide; or{10-[4-(2,5-Dimethyl-1H-pyrrol-1-yl)-3-methoxybenzoyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}[4-(2-hydroxyethyl)-1-piperazinyl]methanoneor a pharmaceutically acceptable salt form thereof.
 10. A pharmaceuticalcomposition comprising a pharmaceutically effective amount of a compoundof claim 1, or a pharmaceutically acceptable salt form thereof, or apharmaceutically acceptable prodrug form thereof, and a pharmaceuticallyacceptable carrier or excipient.
 11. A method for inhibiting orpreventing preterm labor, dysmenorrhea, and endometritis in a mammal,the method comprising administering to a mammal in need thereof apharmaceutically effective amount of a compound of claim 1, apharmaceutically acceptable salt form thereof.